Alkanoic acid derivatives process for their production and use thereof

ABSTRACT

An alkanoic acid derivative useful as a prophylactic or therapeutic agent of diabetes mellitus, hyperlipidemia, impaired glucose tolerance and the like can be provided by a compound represented by the formula 
                         
wherein R 1  is an optionally substituted 5-membered aromatic heterocyclic group; X is a bond and the like; Q is a divalent hydrocarbon group having 1 to 20 carbon atoms; Y is a bond and the like; ring A is an aromatic ring optionally further having 1 to 3 substituents; Z is —(CH 2 ) n -Z 1 -(n is an integer of 1 to 8 and Z 1  is an oxygen atom and the like) and the like; ring B is a pyridine ring optionally further having 1 to 3 substituents, and the like; U is a bond and the like; W is a divalent hydrocarbon group having 1 to 20 carbon atoms; and R 3  is —OH and the like, provided that, when ring B is a benzene ring optionally further having 1 to 3 substituents, U should be a bond, or a salt thereof.

This application is the National Phase filing of International PatentApplication No. PCT/JP01/11611, filed 28 Dec. 2001.

TECHNICAL FIELD

The present invention relates to a novel alkanoic acid derivative havingan excellent pharmaceutical action such as hypoglycemic action,hypolipidemic action and the like, which is useful as a prophylactic ortherapeutic agent of diabetes mellitus, hyperlipidemia, impaired glucosetolerance, inflammatory diseases, arteriosclerosis and the like, as wellas a production method thereof.

The present invention also relates to a prophylactic or therapeuticagent of diabetes mellitus, hyperlipidemia, impaired glucose toleranceand the like, which comprises a novel alkanoic acid derivative.

The present invention further relates to a retinoid-related receptorfunction regulating agent, an insulin sensitizer or the like, whichcomprises a novel alkanoic acid derivative.

BACKGROUND ART

As alkanoic acid derivatives, the compounds described in the followingreferences are known.

-   (1) WO 00/64876 describes, as a PPAR ligand-receptor binder, a    compound represented by the formula:

wherein

are each independently aryl and the like; A is —O— and the like; B is—O— and the like; D is —O— and the like; E is a bond or an ethylenegroup; a, b, c and e are each 0-4; d is 0-5; f is 0-6; R₁, R₃, R₅, R₇,R₉ and R₁₁ are each independently hydrogen and the like; R₂, R₄, R₆, R₈,R₁₀ and R₁₂ are each independently —(CH)_(q)—X; q is 0-3; X is hydrogenand the like; Z is R₂₁O₂C— and the like; R₂₁ is hydrogen and the like.

-   (2) WO 99/20275 describes a method of mediating the activity of    PPAR-γ receptor using a compound represented by the formula:

wherein A is a bond, an oxygen atom, a sulfur atom and the like; B is abond, an oxygen atom, a sulfur atom and the like; D is a bond, an oxygenatom, a sulfur atom and the like; E is a bond and the like; a and n areeach 0-2; b is 0-1; c and e are each 0-4; d and f are each 0-5; R ishydrogen and the like; R′ is hydrogen and the like; R₁ is hydrogen andthe like; R₂ is —(CH₂)_(q)—X and the like; q is 0-3; X is hydrogen andthe like; and Z is R₁O₂C— and the like.

-   (3) WO 92/20350 describes, as a substance capable of mimicking the    action of physiologically active natural polymer, a compound    represented by the formula: Mi-(Mn)n-Mt wherein n is the number of 2    to about 50; Mi, Mn and Mt are

respectively;wherein

are each independently an aromatic carbocycle or an aromaticheterocycle; Ai, Bi, An, Bn, At, Bt, Ti and Tt are each independentlyhydrogen or a substituent; and Xi and Xn are each independently a bondand the like.

-   (4) WO 99/58510 describes, as a substance having a hypoglycemic and    hypolipidemic action, a compound represented by the formula:

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; X is a bond and the like; nis an integer of 1 to 3; Y is an oxygen atom and the like; ring A is abenzene ring optionally further having 1 to 3 substituents; p is aninteger of 1 to 8; R² is a hydrogen atom and the like; q′ is an integerof 0 to 6; m is 0 or 1; R³ is a hydroxy group and the like; and R⁴ andR⁵ are the same or different and each is a hydrogen atom and the like.

Peroxisome proliferator-activated receptor gamma (PPARγ), a member ofthe intranuclear hormone receptor superfamily, which is typicallyexemplified by steroid hormone receptors and thyroid hormone receptors,plays an important role as a master regulator in the differentiation ofadipose cells with its expression induced in the very early stage ofadipose cell differentiation. PPARγ forms a dimer with the retinoid Xreceptor (RXR) by binding to a ligand, and binds to a responsive site ofthe target gene in the nucleus to directly control (activate)transcription efficiency. In recent years, the possibility that15-deoxy-Δ^(12.14) prostaglandin J₂, a metabolite of prostaglandin D₂,serves as an endogenous ligand for PPARγ, has been suggested, and it hasbeen shown that a class of insulin sensitivity enhancing agent,typically exemplified by thiazolidinedione derivatives, possess ligandactivity for PPARγ, and that its potency is proportional to itshypoglycemic action or adipose cell differentiation-promoting, action[Cell, vol. 83, p. 803 (1995): The Journal of Biological Chemistry, vol.270, p. 12953 (1995); Journal of Medicinal Chemistry, vol. 39, p. 655(1996)]. Furthermore, in recent years, it has been shown that 1) PPARγis expressed in cultured cells of human liposarcoma origin, whoseproliferation is ceased by the addition of a PPARγ ligand [Proceedingsof the National Academy of Sciences of the United States of America,vol. 94, p. 237 (1997)], 2) nonsteroidal anti-inflammatory drugs,typically exemplified by indomethacin and fenoprofen, have PPARγ ligandactivity [The Journal of Biological Chemistry, vol. 272, p. 3406(1997)], 3) PPARγ is expressed at high levels in activated macrophages,with the transcription of a gene involved in inflammation inhibited bythe addition of a ligand therefor [Nature, vol. 391, p. 79 (1998)], and4) PPARγ ligands suppress the production of inflammatory cytokines(TNFα, IL-1β, IL-6) by monocytes [Nature, vol. 391, p. 82 (1998)], andthe like.

From the foregoing, there is a demand for development of a novelcompound useful as a prophylactic or therapeutic agent of diabetesmellitus, hyperlipidemia, impaired glucose tolerance, inflammatorydiseases, arteriosclerosis etc., and having pharmaceutically excellentproperties such as low side effects, and the like.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide an alkanoic acidderivative useful as a prophylactic or therapeutic agent of diabetesmellitus, hyperlipidemia, impaired glucose tolerance and the like, and aproduction method thereof.

The present invention relates to the following (1)-(32) and the like.

-   (1) A compound represented by the formula

wherein

-   R¹ is an optionally substituted 5-membered aromatic heterocyclic    group;-   X is a bond, an oxygen atom, a sulfur atom, —CO—, —CS—, —CR⁴(OR⁵)—    or —NR⁶— (R⁴ is a hydrogen atom or an optionally substituted    hydrocarbon group, R⁵ is a hydrogen atom or a hydroxy-protecting    group, R⁶ is a hydrogen atom, an optionally substituted hydrocarbon    group or an amino-protecting group);-   Q is a divalent hydrocarbon group having 1 to 20 carbon atoms;-   Y is a bond, an oxygen atom, a sulfur atom, —SO—, —SO₂—, —NR⁷—,    —CONR⁷— or —NR⁷CO— (R⁷ is a hydrogen atom, an optionally substituted    hydrocarbon group or an amino-protecting group);-   ring A is an aromatic ring optionally further having 1 to 3    substituents;-   Z is —(CH₂)_(n)-Z- or -Z¹-(CH₂)_(n)— (n is an integer of 1 to 8, Z¹    is an oxygen atom, a sulfur atom, —SO—, —SO₂— or —NR¹⁶— (R¹⁶ is a    hydrogen atom or an optionally substituted hydrocarbon group));-   ring B is a pyridine ring, a benzene ring or a naphthalene ring,    each of which optionally further has 1 to 3 substituents;-   U is a bond, an oxygen atom, a sulfur atom, —SO— or —SO₂—;-   W is a divalent hydrocarbon group having 1 to 20 carbon atoms; and-   R³ is —OR⁸ (R⁸ is a hydrogen atom or an optionally substituted    hydrocarbon group) or —NR⁹R¹⁰ (R⁹ and R¹⁰ are the same or different    and each is a hydrogen atom, an optionally substituted hydrocarbon    group, an optionally substituted heterocyclic group or an optionally    substituted acyl group, or R⁹ and R¹⁰ may be bonded to form an    optionally substituted ring);    provided that, when ring B is a benzene ring optionally further    having 1 to 3 substituents, U should be a bond, or a salt thereof.-   (2) The compound of the above-mentioned (1), wherein the 5-membered    aromatic heterocyclic group represented by R¹ is oxazolyl, thiazolyl    or triazolyl.-   (3) The compound of the above-mentioned (1), wherein X is a bond or    —NR⁶— (R⁶ is a hydrogen atom, an optionally substituted hydrocarbon    group or an amino-protecting group).-   (4) The compound of the above-mentioned (1), wherein Q is    C₁₋₆alkylene or C₂₋₆ alkenylene.-   (5) The compound of the above-mentioned (1), wherein Y is a bond, an    oxygen atom or —NR⁷— (R⁷ is a hydrogen atom, an optionally    substituted hydrocarbon group or an amino-protecting group).-   (6) The compound of the above-mentioned (1), wherein the aromatic    ring represented by ring A is a benzene ring, a pyridine ring or an    isoxazole ring.-   (7) The compound of the above-mentioned (1), wherein n is an integer    of 1 to 3 and Z¹ is an oxygen atom or a sulfur atom.-   (8) The compound of the above-mentioned (1), wherein the ring B is a    pyridine ring or a naphthalene ring, each of which optionally    further has 1 to 3 substituents.-   (9) The compound of the above-mentioned (1), wherein U is a bond.-   (10) The compound of the above-mentioned (1), wherein W is a C₁₋₆    alkylene or a C₂₋₆ alkenylene.-   (11) The compound of the above-mentioned (1), wherein R³ is —OR⁸ (R⁸    is a hydrogen atom or an optionally substituted hydrocarbon group.-   (12) The compound of the above-mentioned (1), wherein R¹ is an    oxazolyl, a thiazolyl, a pyrazolyl or a triazolyl, each of which    optionally has 1 to 3 substituents selected from-   1) a C₁₋₁₀ alkyl group optionally having 1 to 3 substituents    selected from a C₁₋₆ alkoxy group optionally substituted by 1 to 3    halogen atoms, a halogen atom, a nitro group, a hydroxy group and an    amino group;-   2) a C₃₋₁₀ cycloalkyl group optionally having 1 to 3 substituents    selected from a C₁₋₆ alkyl group optionally substituted by 1 to 3    halogen atoms, a C₁₋₆ alkoxy group optionally substituted by 1 to 3    halogen atoms, a halogen atom, a nitro group, a hydroxy group and an    amino group;-   3) an aromatic heterocyclic group optionally having 1 to 3    substituents selected from a C₁₋₆ alkyl group optionally substituted    by 1 to 3 halogen atoms, a C₁₋₆ alkoxy group optionally substituted    by 1 to 3 halogen atoms, a halogen atom, a nitro group, a hydroxy    group and an amino group; and-   4) a C₆₋₁₄ aromatic hydrocarbon group optionally having 1 to 3    substituents selected from a C₁₋₆ alkyl group optionally substituted    by 1 to 3 halogen atoms, a C₁₋₆ alkoxy group optionally substituted    by 1 to 3 halogen atoms, a halogen atom, a nitro group, a hydroxy    group and an amino group;-   X is a bond or —NR⁶— wherein R⁶ is a hydrogen atom or an alkyl group    having 1 to 4 carbon atoms;-   Q is a C₁₋₆ alkylene or a C₂₋₆ alkenylene;-   Y is a bond, an oxygen atom or —NR⁷— wherein R⁷ is an    amino-protecting group;-   ring A is a benzene ring, a fused aromatic hydrocarbon ring having 9    to 14 carbon atoms, or a 5- or 6-membered aromatic heterocycle, each    of which optionally further has 1 to 3 substitutents selected from    an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an    alkoxy group having 1 to 4 carbon atoms, an aralkyloxy group having    7 to 10 carbon atoms and a halogen atom;-   Z is —(CH₂)_(n)-Z¹- or -Z¹-(CH₂)_(n)— wherein n is an integer of 1    to 3 and Z¹ is an oxygen atom or a sulfur atom;-   ring B is a pyridine ring or a naphthalene ring, each of which    optionally further has 1 to 3 substituents selected from an alkyl    group having 1 to 4 carbon atoms, an aryl group having 6 to 14    carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon    atoms, an aralkyloxy group having 7 to 10 carbon atoms and a halogen    atom;-   U is a bond or an oxygen atom; and-   W is a C₁₋₆ alkylene or a C₂₋₆ alkenylene;-   R³ is —OR⁸ wherein R⁸ is a hydrogen atom or an alkyl group having 1    to 4 carbon atoms.-   (13) The compound of the above-mentioned (1), which is    2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic    acid;-   2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetic    acid;-   2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]acetic    acid;-   2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]phenyl]acetic    acid;-   2-[2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]acetic    acid; or a salt thereof.-   (14) A prodrug of the compound of the above-mentioned (1) or a salt    thereof.-   (15) A pharmaceutical composition comprising the compound of the    above-mentioned (1) or a salt thereof or a prodrug thereof.-   (16) A prophylactic or therapeutic agent of diabetes mellitus, which    comprises the compound of the above-mentioned (1) or a salt thereof    or a prodrug thereof.-   (17) A prophylactic or therapeutic agent of hyperlipidemia, which    comprises the compound of the above-mentioned (1) or a salt thereof    or a prodrug thereof.-   (18) A prophylactic or therapeutic agent of impaired glucose    tolerance, which comprises the compound of the above-mentioned (1)    or a salt thereof or a prodrug thereof.-   (19) A retinoid-related receptor function regulating agent    comprising the compound of the above-mentioned (1) or a salt thereof    or a prodrug thereof.-   (20) The agent of the above-mentioned (19), which is a ligand for    peroxisome proliferator-activated receptor.-   (21) The agent of the above-mentioned (19), which is a ligand for    retinoid X receptor.-   (22) An insulin sensitizer comprising the compound of the    above-mentioned (1) or a salt thereof or a prodrug thereof-   (23) A method for treating diabetes mellitus in a mammal, which    comprises administering the compound of the above-mentioned (1) or a    salt thereof or a prodrug thereof to said mammal.-   (24) A method for treating hyperlipidemia in a mammal, which    comprises administering the compound of the above-mentioned (1) or a    salt thereof or a prodrug thereof to said mammal.-   (25) A method for treating impaired glucose tolerance in a mammal,    which comprises administering the compound of the    above-mentioned (1) or a salt thereof or a prodrug thereof to said    mammal.-   (26) Use of the compound of the above-mentioned (1) or a salt    thereof or a prodrug thereof for the production of a prophylactic or    therapeutic agent of diabetes mellitus.-   (27) Use of the compound of the above-mentioned (1) or a salt    thereof or a prodrug thereof for the production of a prophylactic or    therapeutic agent of hyperlipidemia.-   (28) Use of the compound of the above-mentioned (1) or a salt    thereof or a prodrug thereof for the production of a prophylactic or    therapeutic agent of impaired glucose tolerance.-   (29) A production method of a compound represented by the formula

wherein

-   R¹ is an optionally substituted 5-membered aromatic heterocyclic    group;-   X is a bond, an oxygen atom, a sulfur atom, —CO—, —CS—, —CR⁴(OR⁵)—    or —NR⁶— (R⁴ is a hydrogen atom or an optionally substituted    hydrocarbon group, R⁵ is a hydrogen atom or a hydroxy-protecting    group, and R⁶ is a hydrogen atom, an optionally substituted    hydrocarbon group or an amino-protecting group);-   Q is a divalent hydrocarbon group having 1 to 20 carbon atoms;-   Y is a bond, an oxygen atom, a sulfur atom, —SO—, —SO₂—, —NR⁷—,    —CONR⁷— or —NR⁷CO— (R⁷ is a hydrogen atom, an optionally substituted    hydrocarbon group or an amino-protecting group);-   ring A is an aromatic ring optionally further having 1 to 3    substituents;-   Z is —(CH₂)_(n)-Z¹- or -Z¹-(CH₂)_(n)— (n is an integer of 1 to 8,    and Z¹ is an oxygen atom, a sulfur atom, —SO—, —SO₂— or —NR¹⁶— (R¹⁶    is a hydrogen atom or an optionally substituted hydrocarbon group));-   ring B is a pyridine ring, a benzene ring or a naphthalene ring,    each of which optionally further has 1 to 3 substituents;-   U is a bond, an oxygen atom, a sulfur atom, —SO— or —SO₂—; and-   W is a divalent hydrocarbon group having 1 to 20 carbon atoms;    provided that, when ring B is a benzene ring optionally further    having 1 to 3 substituents, U should be a bond, or a salt thereof,    which comprises subjecting a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, to ahydrolysis reaction.

-   (30) A production method of a compound represented by the formula

wherein

-   R¹ is an optionally substituted 5-membered aromatic heterocyclic    group;-   X is a bond, an oxygen atom, a sulfur atom, —CO—, —CS—, —CR⁴(OR⁵)—    or —NR⁶— (R⁴ is a hydrogen atom or an optionally substituted    hydrocarbon group, R⁵ is a hydrogen atom or a hydroxy-protecting    group, and R⁶ is a hydrogen atom, an optionally substituted    hydrocarbon group or an amino-protecting group);-   Q is a divalent hydrocarbon group having 1 to 20 carbon atoms;-   Y is a bond, an oxygen atom, a sulfur atom, —SO—, —SO₂—, —NR⁷—,    —CONR⁷— or —NR⁷CO— (R⁷ is a hydrogen atom, an optionally substituted    hydrocarbon group or an amino-protecting group);-   ring A is an aromatic ring optionally further having 1 to 3    substituents;-   Z is —(CH₂)_(n)-Z¹- or -Z¹-(CH₂)_(n)— (n is an integer of 1 to 8,    and Z¹ is an oxygen atom, a sulfur atom, —SO—, —SO₂— or —NR¹⁶— (R¹⁶    is a hydrogen atom or an optionally substituted hydrocarbon group));-   ring B is a pyridine ring, a benzene ring or a naphthalene ring,    each of which optionally further has 1 to 3 substituents;-   U is a bond, an oxygen atom, a sulfur atom, —SO— or —SO₂—; and-   W is a divalent hydrocarbon group having 1 to 20 carbon atoms;    provided that, when ring B is a benzene ring optionally further    having 1 to 3 substituents, U should be a bond, or a salt thereof,    which comprises subjecting a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, to anoxidation reaction.

-   (31) A compound represented by the formula

wherein

-   R¹ is an optionally substituted 5-membered aromatic heterocyclic    group;-   X is a bond, an oxygen atom, a sulfur atom, —CO—, —CS—, —CR⁴(OR⁵)—    or —NR⁶— (R⁴ is a hydrogen atom or an optionally substituted    hydrocarbon group, R⁵ is a hydrogen atom or a hydroxy-protecting    group, and R⁶ is a hydrogen atom, an optionally substituted    hydrocarbon group or an amino-protecting group);-   Q is a divalent hydrocarbon group having 1 to 20 carbon atoms;-   Y is a bond, an oxygen atom, a sulfur atom, —SO—, —SO₂—, —NR⁷—,    —CONR⁷— or —NR⁷CO— (R⁷ is a hydrogen atom, an optionally substituted    hydrocarbon group or an amino-protecting group);-   ring A is an aromatic ring optionally further having 1 to 3    substituents;-   Z is —(CH₂)_(n)-Z¹- or -Z¹-(CH₂)_(n)— (n is an integer of 1 to 8,    and Z¹ is an oxygen atom, a sulfur atom, —SO—, —SO₂— or —NR¹⁶— (R¹⁶    is a hydrogen atom or an optionally substituted hydrocarbon group));-   ring B is a pyridine ring, a benzene ring or a naphthalene ring,    each of which optionally further has 1 to 3 substituents;-   U is a bond, an oxygen atom, a sulfur atom, —SO— or —SO₂—; and-   W is a divalent hydrocarbon group having 1 to 20 carbon atoms;    provided that, when ring B is a benzene ring optionally further    having 1 to 3 substituents, U should be a bond, or a salt thereof.-   (32) A compound represented by the formula

wherein

-   R¹ is an optionally substituted 5-membered aromatic heterocyclic    group;-   X is a bond, an oxygen atom, a sulfur atom, —CO—, —CS—, —CR⁴(OR⁵)—    or —NR⁶— (R⁴ is a hydrogen atom or an optionally substituted    hydrocarbon group, R⁵ is a hydrogen atom or a hydroxy-protecting    group, and R⁶ is a hydrogen atom, an optionally substituted    hydrocarbon group or an amino-protecting group);-   Q is a divalent hydrocarbon group having 1 to 20 carbon atoms;-   Y is a bond, an oxygen atom, a sulfur atom, —SO—, —SO₂—, —NR⁷—,    —CONR⁷— or —NR⁷CO— (R⁷ is a hydrogen atom, an optionally substituted    hydrocarbon group or an amino-protecting group);-   ring A is an aromatic ring optionally further having 1 to 3    substituents;-   Z is —(CH₂)_(n)-Z¹- or -Z¹-(CH₂)_(n)— (n is an integer of 1 to 8,    and Z¹ is an oxygen atom, a sulfur atom, —SO—, —SO₂— or —NR¹⁶— (R¹⁶    is a hydrogen atom or an optionally substituted hydrocarbon group));-   ring B is a pyridine ring, a benzene ring or a naphthalene ring,    each of which optionally further has 1 to 3 substituents;-   U is a bond, an oxygen atom, a sulfur atom, —SO— or —SO₂—; and-   W is a divalent hydrocarbon group having 1 to 20 carbon atoms;    provided that, when ring B is a benzene ring optionally further    having 1 to 3 substituents, U should be a bond, or a salt thereof.

In the formula (I), as the “5-membered aromatic heterocyclic group” ofthe “optionally substituted 5-membered aromatic heterocyclic group”represented by R¹, for example, a 5-membered monocyclic aromaticheterocyclic group containing, besides carbon atoms, 1 to 4 hetero atomsselected from oxygen atom, sulfur atom and nitrogen atom, as a ringconstituting atom, can be mentioned. The monocyclic aromaticheterocyclic group may be condensed with a 6-membered heterocyclecontaining 1 or 2 nitrogen atoms (e.g., pyridine ring), benzene ring andthe like, and such condensed ring is also encompassed in the definitionof R¹.

Specific examples of the “5-membered monocyclic aromatic heterocyclicgroup” include furyl (2-furyl, 3-furyl), thienyl (2-thienyl, 3-thienyl),pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl,0.5-isoxazolyl), isothiazolyl (3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl),oxazolyl (2-oxazolyl-4-oxazolyl, 5-oxazolyl), oxadiazolyl(1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl(1,3,4-thiadiazol-2-yl), triazolyl (1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl-1,2,3-triazol-4-yl), tetrazolyl (tetrazol-1-yl,tetrazol-5-yl) and the like.

Specific examples of the condensed ring formed by the above-mentioned“5-membered monocyclic aromatic heterocyclic group” include2-benzoxazolyl, 2-benzothiazolyl, benzimidazol-1-yl, benzimidazol-2-yl,indol-1-yl, indol-3-yl, 1H-indazol-3-yl and the like.

The 5-membered aromatic heterocyclic group represented by R¹ ispreferably oxazolyl, thiazolyl, pyrazolyl, triazolyl and the like, morepreferably oxazolyl, thiazolyl, triazolyl and the like.

The “5-membered aromatic heterocyclic group” represented by R¹ may have1 to 4, preferably 1 to 3, substituents at substitutable positions. Assuch substituent, for example, “halogen atom”, “nitro group”,“optionally substituted aliphatic hydrocarbon group”, “optionallysubstituted alicyclic hydrocarbon group”, “optionally substitutedaromatic hydrocarbon group”, “optionally substituted aromaticheterocyclic group”, “optionally substituted non-aromatic heterocyclicgroup”, “optionally substituted nonaromatic heterocyclic group”,“optionally substituted acyl group”, “optionally substituted aminogroup”, “optionally substituted hydroxy group”, “optionally substitutedthiol group”, “optionally esterified or amidated carboxyl group” and thelike can be mentioned.

As the “halogen atom”, fluorine, chlorine, bromine and iodine can bementioned, with preference given to fluorine and chlorine.

As the aliphatic hydrocarbon group of the “optionally substitutedaliphatic hydrocarbon group”, a straight chain or branched aliphatichydrocarbon group having 1 to 15 carbon atoms, such as alkyl group,alkenyl group, alkynyl group and the like can be mentioned.

Preferable examples of the alkyl group include an alkyl group having 1to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and thelike.

Preferable examples of the alkenyl group include an alkenyl group having2 to 10 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl,1-octenyl and the like.

Preferable examples of the alkynyl group include an alkynyl group having2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,1-heptynyl, 1-octynyl and the like.

As the substituent of the “optionally substituted aliphatic hydrocarbongroup”, for example, a cycloalkyl group having 3 to 10 carbon atoms, anaryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl etc.), anaromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl,thiazolyl etc.), a non-aromatic heterocyclic group (e.g.,tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl,piperazinyl etc.), an aralkyl group having 7 to 9 carbon atoms, an aminogroup, an amino group mono- or di-substituted by alkyl group having 1 to4 carbon atoms or acyl group having 2 to 8 carbon atoms (e.g., alkanoylgroup etc.), an amidino group, an acyl group having 2 to 8 carbon atoms(e.g., alkanoyl group etc.), a carbamoyl group, a carbamoyl group mono-or di-substituted by alkyl group having 1 to 4 carbon atoms, a sulfamoylgroup, a sulfamoyl group mono- or di-substituted by alkyl group having 1to 4 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to8 carbon atoms, a hydroxy group, a C₁₋₆ alkoxy group optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine etc.), a C₂₋₅ alkenyloxy group optionally substituted by 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine etc.), acycloalkyloxy group having 3 to 7 carbon atoms, an aralkyloxy grouphaving 7 to 9 carbon atoms, an aryloxy group having 6 to 14 carbon atoms(e.g., phenyloxy, naphthyloxy etc.), a thiol group, a C₁₋₆ alkylthiogroup optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine etc.), an aralkylthio group having 7 to 9carbon atoms, an arylthio group having 6 to 14 carbon atoms (e.g.,phenylthio, naphthylthio etc.), a sulfo group, a cyano group, an azidegroup, a nitro group, a nitroso group, a halogen atom (e.g., fluorine,chlorine, bromine, iodine) and the like can be mentioned. The number ofsubstituent is, for example, 1 to 3.

As the alicyclic hydrocarbon group of the “optionally substitutedalicyclic hydrocarbon group”, saturated or unsaturated alicyclichydrocarbon group having 3 to 12 carbon atoms, such as cycloalkyl group,cycloalkenyl group, cycloalkadienyl group and the like, can bementioned.

Preferable examples of the cycloalkyl group include cycloalkyl grouphaving 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and thelike.

Preferable examples of the cycloalkenyl group include cycloalkenyl grouphaving 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl,3-cyclopenten-1-yl 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.

Preferable examples of the cycloalkadienyl group include cycloalkadienylgroup having 4 to 10 carbon atoms, such as 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.

Preferable examples of the aromatic hydrocarbon group of the “optionallysubstituted aromatic hydrocarbon group” include aromatic hydrocarbongroup having 6 to 14 carbon atoms (i.e., aryl group, such as phenyl,naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and thelike). Of these, phenyl, 1-naphthyl, 2-naphthyl and the like arepreferable.

As the aromatic heterocyclic group of the “optionally substitutedaromatic heterocyclic group”, for example, a monocyclic, bicyclic ortricyclic aromatic heterocyclic group containing, besides carbon atoms,1 to 5 hetero atoms selected from oxygen atom, sulfur atom and nitrogenatom, as a ring constituting atom, and the like can be mentioned.

Preferable examples of the monocyclic aromatic heterocyclic groupinclude furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl (1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), furazanyl, thiadiazolyl(1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl(1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl and the like.

Preferable examples of the bicyclic or tricyclic aromatic heterocyclicgroup include benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl,isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzothiazoly,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acrydinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,indolizinyl, pyrrolo[1,2-b]pyridaziriyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, and the like.

As the non-aromatic heterocyclic group of the “optionally substitutednon-aromatic heterocyclic group”, for example, a C₂₋₁₀ non-aromaticheterocyclic group containing, besides carbon atoms, 1 to 3 hetero atomsselected from oxygen atom, sulfur atom and nitrogen atom, as a ringconstituting atom, and the like can be mentioned. Preferable examples ofthe non-aromatic heterocyclic group include oxiranyl, azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl,morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidino,morpholino, thiomorpholino and the like.

As the substituent of the aforementioned “optionally substitutedalicyclic hydrocarbon group”, “optionally substituted aromatichydrocarbon group”, “optionally substituted aromatic heterocyclic group”and “optionally substituted non-aromatic heterocyclic group”, forexample, a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogenatoms (e.g., fluorine, chlorine, bromine, iodine etc.), a C₂₋₆ alkenylgroup optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine etc.), a cycloalkyl group having 3 to 10carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms(namely, aryl group) (e.g., phenyl, naphthyl etc.), an aromaticheterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyletc.), a non-aromatic heterocyclic group (e.g., tetrahydrofuryl,morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl etc.),an aralkyl group having 7 to 9 carbon atoms, an amino group, an aminogroup mono- or di-substituted by alkyl group having 1 to 4 carbon atomsor acyl group having 2 to 8 carbon atoms (e.g., alkanoyl group etc.), anamidino group, an acyl group having 2 to 8 carbon atoms (e.g., alkanoylgroup etc.), a carbamoyl group, a carbamoyl group mono- ordi-substituted by alkyl group having 1 to 4 carbon atoms, a sulfamoylgroup, a sulfamoyl group mono- or di-substituted by alkyl group having 1to 4 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to8 carbon atoms, a hydroxy group, a C₁₋₆ alkoxy group optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine etc.), a C₂₋₅ alkenyloxy group optionally substituted by 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine etc.), acycloalkyloxy group having 3 to 7 carbon atoms, an aralkyloxy grouphaving 7 to 9 carbon atoms, an aryloxy group having 6 to 14 carbon atoms(e.g., phenyloxy, naphthyloxy etc.), a thiol group, a C₁₋₆ alkylthiogroup optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine etc.), an aralkylthio group having 7 to 9carbon atoms, an arylthio group having 6 to 14 carbon atoms (e.g.,phenylthio, naphthylthio etc.), a sulfo group, a cyano group, an azidegroup, a nitro group, a nitroso group, a halogen atom (e.g., fluorine,chlorine, bromine, iodine) and the like can be mentioned. The number ofsubstituent is, for example, 1 to 3.

As the acyl group of the “optionally substituted acyl group”, an acylgroup having 1 to 13 carbon atoms, which is, besides formyl,specifically a group represented by the formula: —COR¹¹, —SO₂R¹¹, —SOR¹¹or —PO₃R¹¹R¹² wherein R¹¹ and R¹² are the same or different and each isa hydrocarbon group or an aromatic heterocyclic group, and the like canbe mentioned.

As the hydrocarbon group represented by R¹¹ or R¹², for example,aliphatic hydrocarbon group, alicyclic hydrocarbon group,alicyclic-aliphatic hydrocarbon group, aromatic-aliphatic hydrocarbongroup, aromatic hydrocarbon group can be mentioned. These hydrocarbongroups preferably have 1 to 15 carbon atoms.

As used herein, as the aliphatic hydrocarbon group, alicyclichydrocarbon group and aromatic hydrocarbon group, those exemplified asthe aforementioned substituent for R¹ can be mentioned.

As the alicyclic-aliphatic hydrocarbon group, for example, one whereinthe aforementioned alicyclic hydrocarbon group and aliphatic hydrocarbongroup are bonded (e.g., cycloalkyl-alkyl group, cycloalkenyl-alkyl groupetc.) can be mentioned. Of these, an alicyclic-aliphatic hydrocarbongroup having 4 to 9 carbon atoms is preferable. Preferable examples ofalicyclic-aliphatic hydrocarbon group include cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl,2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl,2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl,cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl and the like.

As the aromatic-aliphatic hydrocarbon group, for example, anaromatic-aliphatic hydrocarbon group having 7 to 13 carbon atoms (e.g.,aralkyl group having 7 to 13 carbon atoms, arylalkenyl group having 8 to13 carbon atoms, etc.) and the like can be mentioned. Preferableexamples of the aromatic-aliphatic hydrocarbon group include phenylalkylhaving 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl,1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl and the like;naphthylalkyl having 11 to 13 carbon atoms such as α-naphthylmethyl,α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl and the like;phenylalkenyl having 8 to 10 carbon atoms such as styryl and the like;naphthylalkenyl having 12 or 13 carbon atoms such as 2-(2-naphthylvinyl)and the like; and the like.

The hydrocarbon group represented by R¹¹ or R¹² is preferably an alkylgroup having 1 to 10 carbon atoms, an alkenyl group having 2 to 10carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, acycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6to 14 carbon atoms and the like.

As the aromatic heterocyclic group represented by R¹¹ or R¹², forexample, a 5 to 7-membered monocyclic aromatic heterocyclic groupcontaining, besides carbon atoms, 1 to 4 hetero atoms selected fromoxygen atom, sulfur atom and nitrogen atom, as a ring constituting atom,and a condensed ring group thereof can be mentioned. As the condensedring group, for example, a group wherein such 5 to 7-membered monocyclicaromatic heterocyclic group and a 6-membered ring containing 1 or 2nitrogen atoms (e.g., pyridine), a benzene ring or a 5-membered ringcontaining one sulfur atom are condensed, and the like can be mentioned.

Preferable examples of the aromatic heterocyclic group include pyridyl(2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl, (2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl(3-pyridazinyl, 4-pyridazinyl), pyrazinyl (2-pyrazinyl), pyrrolyl(1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl), isothiazolyl-(3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl),oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), oxadiazolyl(1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl(1,3,4-thiadiazol-2-yl), triazolyl (1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl,1,2,3-triazol-4-yl), tetrazolyl (tetrazol-1-yl, tetrazol-5-yl), quinolyl(2-quinolyl, 3-quinolyl, 4-quinolyl), quinazolyl (2-quinazolyl,4-quinazolyl), quinoxalyl (2-quinoxalyl), benzoxazolyl-(2-benzoxazolyl),benzothiazolyl (2-benzothiazolyl), benzimidazolyl (benzimidazol-1-yl,benzimidazol-2-yl), indolyl (indol-1-yl, indol-3-yl), indazolyl(1H-indazol-3-yl), pyrrolopyrazinyl (1H-pyrrolo[2,3-b]pyrazin-2-yl),pyrrolopyridinyl (1H-pyrrolo[2,3-b]pyridin-6-yl), imidazopyridinyl(imidazo[1,2-a]pyridin-2-yl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl), imidazopyrazinyl(1H-imidazo[4,5-b]pyrazin-2-yl), oxophthalazinyl(1-oxo-2-(1H)-phthalazinyl) and the like. Of these, thienyl, furyl,pyridyl and the like are preferable.

Preferable examples of the acyl group include acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, nicotinoyl, isonicotinoyl and the like.

The acyl group may have 1 to 3 substituents at substitutable positionsthereof. As such substituent, for example, a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine etc.), a C₁₋₆ alkoxy group optionally substituted by 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine etc.), ahalogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), nitro,hydroxy, amino and the like can be mentioned.

As the “optionally substituted amino group”, for example, an amino groupoptionally mono- or di-substituted by alkyl group having 1 to 10 carbonatoms, alkenyl group having 2 to 10 carbon atoms, cycloalkyl grouphaving 3 to 10 carbon atoms, cycloalkenyl group having 3 to 10 carbonatoms, aryl group having 6 to 14 carbon atoms or acyl group having 1 to13 carbon atoms and the like can be mentioned. As these groups, thoseexemplified as the aforementioned substituent for R¹ can be mentioned.The acyl group having 1 to 13 carbon atoms is preferably alkanoyl grouphaving 2 to 10 carbon atoms, arylcarbonyl group having 7 to 13 carbonatoms and the like.

Preferable examples of the substituted amino group include methylamino,dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino,diallylamino, cyclohexylamino, acetylamino, propionylamino,benzoylamino, phenylamino, N-methyl-N-phenylamino and the like.

As the “optionally substituted hydroxy group”, for example, a hydroxygroup optionally substituted by optionally Substituted alkyl grouphaving 1 to 10 carbon atoms, optionally substituted alkenyl group having2 to 10 carbon atoms, optionally substituted aralkyl group having 7 to13 carbon atoms, optionally substituted acyl group having 7 to 13 carbonatoms or optionally substituted aryl group having 6 to 14 carbon atomscan be mentioned. As these alkyl group, alkenyl group, acyl group andaryl group, those exemplified as the aforementioned substituent for R¹can be mentioned. As the “aralkyl group having 7 to 13 carbon atoms”,those exemplified as the aforementioned hydrocarbon group represented byR¹¹ and R¹² can be mentioned.

As the substituent that the aforementioned alkyl group, alkenyl group,aralkyl group, acyl group and aryl group may have, for example, ahalogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), an alkoxygroup having 1 to 3 carbon atoms and the like can be mentioned. Thenumber of substituent is, for example; 1 or 2.

As the substituted hydroxy group, for example, alkoxy group, alkenyloxygroup, aralkyloxy group, acyloxy group, aryloxy group and the like, eachoptionally substituted, can be mentioned.

Preferable examples of the alkoxy group include an alkoxy group having 1to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy,neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy,cyclopentyloxy, cyclohexyloxy and the like.

Preferable examples of the alkenyloxy group include an alkenyloxy grouphaving 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy,3-hexenyloxy, 2-cyclopentenylinethoxy, 2-cyclohexenylmethoxy and thelike.

Preferable examples of the aralkyloxy group include an aralkyloxy grouphaving 7 to 10 carbon atoms, such as phenyl-C₁₋₄ alkyloxy (e.g.,benzyloxy, phenethyloxy etc.) and the like.

Preferable examples of the acyloxy group include an acyloxy group having2 to 13 carbon atoms, more preferably an alkanoyloxy having 2 to 4carbon atoms (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxyetc.) and the like.

Preferable examples of the aryloxy group include, an aryloxy grouphaving 6 to 14 carbon atoms, such as phenoxy, naphthyloxy and the like.

The above-mentioned alkoxy group, alkenyloxy group, aralkyloxy group,acyloxy group and aryloxy group may have 1 or 2 substituents atsubstitutable positions thereof. As such substituent, for example, ahalogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), a C₁₋₆alkoxy group optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine etc.), hydroxy group, nitro group,amino group and the like can be mentioned. As the substituted aryloxygroup, for example, 4-chlorophenoxy, 2-methoxyphenoxy and the like canbe mentioned.

As the “optionally substituted thiol group”, for example, a thiol groupoptionally substituted by alkyl group having 1 to 10 carbon atoms,cycloalkyl group having 3 to 10 carbon atoms, aralkyl group having 7 to13 carbon atoms, acyl group having 2 to 13 carbon atoms, an aryl grouphaving 6 to 14 carbon atoms, heteroaryl group and the like can bementioned. As these alkyl group, cycloalkyl group, acyl group and arylgroup, those exemplified as the aforementioned substituent for R¹ can bementioned. As the aralkyl group, those exemplified as the aforementionedhydrocarbon group represented by R¹¹ and R¹² can be mentioned.Preferable examples of the heteroaryl group include pyridyl (e.g.,2-pyridyl, 3-pyridyl etc.), imidazolyl (e.g., 2-imidazolyl etc.),triazolyl (e.g., 1,2,4-triazol-5-yl etc.) and the like.

As the substituted thiol group, for example, alkylthio, cycloalkylthio,aralkylthio, acylthio, arylthio, heteroarylthio and the like can bementioned.

Preferable examples of the alkylthio group include an alkylthio grouphaving 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio,pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio,nonylthio and the like.

Preferable examples of the cycloalkylthio group include a cycloalkylthiogroup having 3 to 10 carbon atoms, such as cyclobutylthio,cyclopentylthio, cyclohexylthio and the like.

Preferable examples of the aralkylthio group include an aralkylthiogroup having 7 to 10 carbon atoms such as phenyl-C₁₋₄ alkylthio (e.g.,benzylthio, phenethylthio etc.) and the like.

Preferable examples of the acylthio group include acylthio group having2 to 13 carbon atoms, more preferably alkanoylthio group having 2 to 4carbon atoms (e.g., acetylthio, propionylthio, butyrylthio,isobutyrylthio etc.) and the like.

Preferable examples of the arylthio group include an arylthio grouphaving 6 to 14 carbon atoms, such as phenylthio, naphthylthio and thelike.

Preferable examples of the heteroarylthio group include pyridylthio(e.g., 2-pyridylthio, 3-pyridylthio), imidazolylthio (e.g.,2-imidazolylthio), triazolylthio (e.g., 1,2,4-triazol-5-ylthio) and thelike.

As the esterified carboxyl group of the optionally esterified carboxylgroup, for example, alkoxycarbonyl group having 2 to 5 carbon atoms(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyletc.), aralkyloxycarbonyl group having 8 to 10 carbon atoms (e.g.,benzyloxycarbonyl etc.), C₇₋₁₅ aryloxycarbonyl group optionallysubstituted by 1 or 2 alkyl group having 1 to 3 carbon atoms (e.g.,phenoxycarbonyl, p-tolyloxycarbonyl etc.) and the like can be mentioned.

As the amidated carboxyl group of the optionally amidated carboxylgroup, a group represented by the formula: —CON(R¹³)(R¹⁴) wherein R¹³and R¹⁴ are the same or different and each is hydrogen atom, optionallysubstituted hydrocarbon group or optionally substituted heterocyclicgroup, can be mentioned.

Here, as the hydrocarbon group of the “optionally substitutedhydrocarbon, group” represented by R¹³ and R¹⁴, those exemplified forthe aforementioned R¹¹ and R¹² can be mentioned. As the heterocyclicgroup of the “optionally substituted heterocyclic group” represented byR¹³ and R¹⁴, aromatic heterocyclic group and non-aromatic heterocyclicgroup exemplified as the substituent for R¹ can be mentioned.

The hydrocarbon group and heterocyclic group may have 1 to 3substituents at substitutable positions thereof. As such substituent,for example, halogen atom (e.g., fluorine, chlorine, bromine, iodineetc.), C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine etc.), C₁₋₆ alkoxy groupoptionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine etc.), nitro group, hydroxy group, amino groupand the like can be mentioned.

The substituent for R¹ is preferably

-   1) C₁₋₁₀ (preferably C₁₋₄) alkyl group optionally having 1 to 3    substituents selected from C₁₋₆ alkoxy group optionally substituted    by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine    etc.), halogen atom (e.g., fluorine, chlorine, bromine, iodine    etc.), nitro group, hydroxy group and amino group;-   2) C₃₋₁₀ (preferably C₃₋₇) cycloalkyl group optionally having 1 to 3    substituents selected from C₁₋₆ alkyl group optionally substituted    by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine    etc.), C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen    atoms (e.g., fluorine, chlorine, bromine, iodine etc.), halogen atom    (e.g., fluorine, chlorine, bromine, iodine etc.), nitro group,    hydroxy group and amino group;-   3) aromatic heterocyclic group (preferably furyl, thienyl, pyridyl,    pyrazinyl etc.) optionally having 1 to 3 substituents selected from    C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms    (e.g., fluorine, chlorine, bromine, iodine etc.), C₁₋₆ alkoxy group    optionally substituted by 1 to 3 halogenatoms (e.g., fluorine,    chlorine, bromine, iodine etc.), halogen atom (e.g., fluorine,    chlorine, bromine, iodine etc.), nitro group, hydroxy group and    amino group;-   14) C₆₋₁₄ aromatic hydrocarbon group (preferably, phenyl, naphthyl    etc.) optionally having 1 to 3 substituents selected from C₁₋₆ alkyl    group optionally substituted by 1 to 3 halogen atoms (e.g.,    fluorine, chlorine, bromine, iodine etc.), C₁₋₆ alkoxy group    optionally substituted by 1 to 63 halogen atoms (e.g., fluorine,    chlorine, bromine, iodine etc.), halogen atom (e.g., fluorine,    chlorine, bromine, iodine etc.), nitro group, hydroxy group and    amino group, and the like.

The number of substituent for R¹ is, for example, 1 to 3, preferably 1or 2.

The substituent for R¹ is more preferably an alkyl group having 1 to 4carbon atoms, furyl, thienyl, phenyl, naphthyl and the like.

R¹ is preferably oxazolyl, thiazolyl, pyrazolyl or triazolyl, each ofwhich optionally has 1 to 3 substituents selected from

-   1) C₁₋₁₀ (preferably C₁₋₄) alkyl group optionally having 1 to 3    substituents selected from C₁₋₆ alkoxy group optionally substituted    by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine    etc.), halogen atom (e.g., fluorine, chlorine, bromine, iodine    etc.), nitro group, hydroxy group and amino group;-   2) C₃₋₁₀ (preferably C₃₋₇) cycloalkyl group optionally having 1 to 3    substituents selected from C₁₋₆ alkyl group optionally substituted    by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine    etc.), C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen    atoms (e.g., fluorine, chlorine, bromine, iodine etc.), halogen atom    (e.g., fluorine, chlorine, bromine, iodine etc.), nitro group,    hydroxy group and amino group;-   3) aromatic heterocyclic group (preferably furyl, thienyl, pyridyl,    pyrazinyl etc.) optionally having 1 to 3 substituents selected from    C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms    (e.g., fluorine, chlorine, bromine, iodine etc.), C₁₋₆ alkoxy group    optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,    chlorine, bromine, iodine etc.), halogen atom (e.g., fluorine,    chlorine, bromine, iodine etc.), nitro group, hydroxy group sand    amino group; and-   4) C₆₋₁₄ aromatic hydrocarbon group (preferably phenyl, naphthyl    etc.) optionally having 1 to 3 substituents selected from C₁₋₆ alkyl    group optionally substituted by 1 to 3 halogen atoms (e.g.,    fluorine, chlorine, bromine, iodine etc.), C₁₋₆ alkoxy group    optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,    chlorine, bromine, iodine etc.), a halogen atom (e.g., fluorine,    chlorine, bromine, iodine etc.), nitro group, hydroxy group and    amino group.

R¹ is more preferably oxazolyl, thiazolyl or triazolyl, each of whichoptionally has 1 or 2 substituents selected from alkyl group having 1 to3 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, furyl,thienyl, phenyl and naphthyl.

In the formula (I), X is a bond, an oxygen atom, a sulfur atom, —CO—,—CS—, —CR⁴(R⁵)— or —NR⁶— (R⁴ is a hydrogen atom or an optionallysubstituted hydrocarbon group, R⁵ is a hydrogen atom or ahydroxy-protecting group, and R⁶ is a hydrogen atom, an optionallysubstituted hydrocarbon group or an amino-protecting group). X ispreferably a bond, —CR⁴(OR⁵)— or —NR⁶— (the symbols are as definedabove), more preferably a bond or —NR⁶— (R⁶ is as defined above).Particularly preferably, X is a bond or —NR⁶— wherein R⁶ is a hydrogenatom or an alkyl group having 1 to 4 carbon atoms.

As the “optionally substituted hydrocarbon group” represented by R⁴ andR⁶, those exemplified for the aforementioned R¹³ and R¹⁴ can bementioned. The “optionally substituted hydrocarbon group” is preferablyan alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like,which may be substituted. The alkyl group may have 1 to 3 substituentsat substitutable positions thereof. As such substituent, for example,halogen atom (e.g., fluorine, chlorine, bromine, iodine), alkoxy group,having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, t-butoxy etc.), hydroxy, nitro, amino,acyl group having 1 to 4 carbon atoms (e.g., alkanoyl group having 1 to4 carbon atoms such as formyl, acetyl, propionyl etc.), and the like canbe mentioned.

R⁴ and R⁶ are each preferably a hydrogen atom or an alkyl group having 1to 4 carbon atoms.

As the hydroxy-protecting group represented by R⁵, for example, C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl etc.),phenyl, trityl, C₇₋₁₀ aralkyl (e.g., benzyl etc.), formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl etc.), benzoyl, C₇₋₁₀aralkyl-carbonyl (e.g., benzylcarbonyl etc.), 2-tetrahydropyranyl,2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl, triethylsilyl,dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyletc.), C₂₋₆ alkenyl (e.g., 1-allyl etc.) and the like can be mentioned.These groups may be substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine etc.), C₁₋₆ alkyl (e.g., methyl, ethyl, propyletc.), C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy etc.) or nitro andthe like.

As the amino-protecting group represented by R⁶, for example, formyl,C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl etc.), C₁₋₆ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl etc.),benzoyl, C₇₋₁₀ aralkyl-carbonyl (e.g., benzylcarbonyl etc.), C₇₋₁₄aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyletc.), trityl, phthaloyl, N,N-dimethylaminomethylene, silyl (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl etc.), C₂₋₆ alkenyl(e.g., 1-allyl etc.) and the like can be mentioned. These groups may besubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine etc.), C₁₋₆-alkoxy (e.g., methoxy, ethoxy, propoxy etc.) or nitroand the like.

As the “divalent hydrocarbon group having 1 to 20 carbon atoms”represented by Q in the formula (I), for example, “divalent acyclichydrocarbon group”, “divalent cyclic hydrocarbon group”, a divalentgroup obtained by combining one or more kinds of “divalent acyclichydrocarbon groups” and one or more kinds of “divalent cyclichydrocarbon groups” can be mentioned.

Here, as the “divalent acyclic hydrocarbon group”, for example, alkylenehaving 1 to 20 carbon atoms, alkenylene having 2 to 20 carbon atoms,alkynylene having 2 to 20 carbon atoms and the like can be mentioned.

As the “divalent cyclic hydrocarbon group”, a divalent group obtained byremoving optional two hydrogen atoms from cycloalkane having 5 to 20carbon atoms, cycloalkene having 5 to 20 carbon atoms or aromatichydrocarbon having 6 to 18 carbon atoms (e.g., benzene, naphthalene,indene, anthracene etc.), and the like can be mentioned. Examplesthereof include 1,2-cyclopentylene, 1,3-cyclopentylene,1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene,1,2-cycloheptylene, 1,3-cycloheptylene, 1,4-cycloheptylene,3-cyclohexen-1,4-ylene, 3-cyclohexen-1,2-ylene,2,5-cyclohexadien-1,4-ylene, 1,2-phenylene, 1,3-phenylene,1,4-phenylene, 1,4-naphthylene, 1,6-naphthylene, 2,6-naphthylene,2,7-naphthylene, 1,5-indenylene, 2,5-indenylene and the like.

Q is preferably a divalent hydrocarbon group having 1 to 6 carbon atoms.Particularly,

-   (1) C₁₋₆ alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,    —(CH₂)₅—, —(CH₂)₆—, —CH(CH₃)—, —C(CH₃)₂—, —(CH(CH₃))₂—,    —(CH₂)₂C(CH₃)₂—; —(CH₂)₃C(CH₃)₂— etc.);-   (2) C₂₋₆ alkenylene (e.g., —CH═CH—, —CH₂—CH═CH—, —C(CH₃)₂—CH═CH—,    —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂—    etc.);-   (3) C₂₋₆ alkynylene (e.g., —C≡C—, —CH₂—C≡C—, —CH₂—C≡C—CH₂—CH₂— etc.)    and the like are preferable.

Q is particularly preferably C₁₋₆ alkylene or C₂₋₆ alkenylene, of which—CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH═CH— and the like arepreferable.

In the formula (I), Y is a bond, an oxygen atom, a sulfur atom, —SO—,—SO₂—, —NR⁷—, —CONR⁷— or —NR⁷CO— (R⁷ is a hydrogen atom, an optionallysubstituted hydrocarbon group or an amino-protecting group). Y ispreferably a bond, an oxygen atom, a sulfur atom, —NR⁷— or —NR⁷CO— (R⁷is as defined above), more preferably a bond, oxygen atom or —NR⁷— (R⁷is as defined above). Particularly preferably, Y is a bond or oxygenatom.

As the “optionally substituted hydrocarbon group” represented by R⁷,those exemplified for the aforementioned R¹³ and R¹⁴ can be mentioned.As the amino-protecting group represented by R⁷, those exemplified forthe aforementioned R⁶ can be mentioned. Of these, C₁₋₆ alkoxy-carbonyland the like are preferable. R⁷ is preferably a hydrogen atom.

As the “aromatic ring” of the “aromatic ring optionally further having 1to 3 substituents” represented by ring A in the formula (I), forexample, benzene ring, fused aromatic hydrocarbon ring, 5- or 6-memberedaromatic heterocycle, fused aromatic heterocycle and the like can bementioned.

Here, as the “fused aromatic hydrocarbon ring”, for example, fusedaromatic hydrocarbon having 9 to 14 carbon atoms and the like can bementioned. Specifically, naphthalene, indene, fluorene, anthracene andthe like can be mentioned.

As the “5- or 6-membered aromatic heterocycle”, for example, a 5- or6-membered aromatic heterocycle containing, besides carbon atoms, 1 to 3hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom,and the like can be mentioned. Specifically, thiophene, furan, pyrrole,imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazle, 1,2,4-thiadiazole, 1,3,4-thiadiazole, furazan and thelike can be mentioned.

As the “fused aromatic heterocycle”, for example, a 9- to 14-membered(preferably 9- or 10-membered) fused aromatic heterocycle containing,besides carbon atoms, 1 to 4 hetero atoms selected from nitrogen atom,sulfur atom and oxygen atom, and the like can be mentioned.Specifically, benzofuran, benzothiophene, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, isoquinoline,quinoline, indole, quinoxaline, phenanthridine, phenothiazine,phenoxazine, phthalazine, naphthyridine, quinazolin, cinnoline,carbazole, β-carboline, acridine, phenazine, phthalimide and the likecan be mentioned.

The “aromatic ring” is preferably a benzene ring, a fused aromatichydrocarbon ring having 9 to 14 carbon atoms (preferably naphthaleneetc.), a 5- or 6-membered aromatic heterocycle (preferably pyridine,oxazole, isoxazole, thiazole, oxadiazole etc.) and the like. The“aromatic ring” is more preferably a benzene ring, a pyridine ring or anisoxazole ring.

When the aromatic ring represented by ring A in the formula (I) is abenzene ring or a pyridine ring, the relationship between Y and Z, whichare substituents on the ring A, is preferably meta position and paraposition, more preferably para position.

That is, when the aromatic ring represented by ring A in the formula (I)is a benzene ring,

is preferably

more preferably

In addition, when the aromatic ring represented by ring A is a pyridinering,

is preferably

more preferably

As the “substituent” of the “aromatic ring optionally further having 1to 3 substituents” represented by ring A, optionally substitutedaliphatic hydrocarbon group (preferably alkyl group), optionallysubstituted hydroxy group, halogen atom, optionally substituted acylgroup, nitro group, optionally substituted amino group and the like canbe mentioned. As these substituents, those exemplified as thesubstituent for R¹ can be used. The substituent of the ring A ispreferably an alkyl group having 1 to 4 carbon atoms, hydroxy group, analkoxy group having 1 to 4 carbon atoms, an aralkyloxy group having 7 to10 carbon atoms (preferably benzyloxy) or a halogen atom (preferablyfluorine, chlorine).

Accordingly, ring A is preferably a benzene ring, a fused aromatichydrocarbon ring having 9 to 14 carbon atoms or a 5- or 6-memberedaromatic heterocycle, each of which optionally further has 1 to 3substituents selected from alkyl group having 1 to 4 carbon atoms,hydroxy group, alkoxy group having 1 to 4 carbon atoms, aralkyloxy grouphaving 7 to 10 carbon atoms and halogen atom.

In the formula (I), Z is —(CH₂)_(n)-Z¹- or -Z¹-(CH₂)_(n)— (n is aninteger of 1 to 8 and Z¹ is an oxygen atom, a sulfur atom, —SO—, —SO₂—or —NR¹⁶— (R¹⁶ is a hydrogen atom or an optionally substitutedhydrocarbon group).

As the “optionally substituted hydrocarbon group” represented by R¹⁶,those exemplified for the aforementioned R¹³ and R¹⁴ can be mentioned.

The “n” is preferably an integer of 1 to 3.

Z¹ is preferably an oxygen atom or a sulfur atom.

Z is preferably —(CH₂)_(n)-Z¹- or -Z¹-(CH₂)_(n)— (more preferably—(CH₂)_(n)-Z¹-), n is an integer of 1 to 3, and Z¹ is an oxygen atom ora sulfur atom,

In the formula (I), ring B is a pyridine ring, benzene ring ornaphthalene ring, each of which optionally further has 1 to 3substituents.

When ring B in the formula (I) is a pyridine ring optionally furtherhaving 1 to 3 substituents, the relationship between Z and U, which aresubstituents on the ring B, may be any of ortho position, meta positionand para position, preferably ortho position or meta position.

That is, when ring B is a pyridine ring,

is preferably

more preferably

When ring B in the formula (I) is a benzene ring optionally furtherhaving 1 to 3 substituents, the relationship between Z and U, which aresubstituents on the ring B, is preferably ortho position or metaposition, particularly preferably ortho position.

That is, when ring B is a benzene ring,

is preferably

more preferably

when ring B is a naphthalene ring,

is preferably

The ring B is preferably a pyridine ring or a naphthalene ring, each ofwhich optionally further has 1 to 3 substituents, more preferably apyridine ring optionally further having 1 to 3 substituents.

As the “substituent” in the ring B, for example, an optionallysubstituted aliphatic hydrocarbon group (preferably alkyl group), anoptionally substituted aromatic hydrocarbon group, an optionallysubstituted hydroxy group, a halogen atom, an optionally substitutedacyl group, a nitro group, an optionally substituted amino group and thelike can be mentioned. As these substituents, those exemplified as thesubstituent for R¹ can be used. The substituent for ring B is preferablyan alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 14carbon atoms (preferably phenyl group), a hydroxy group, an alkoxy grouphaving 1 to 4 carbon atoms, an aralkyloxy group having 7 to 10 carbonatoms (preferably benzyloxy) or a halogen atom (preferably fluorine,chlorine, bromine).

Accordingly ring B is particularly preferably a pyridine ring or anaphthalene ring, each of which optionally further has 1 to 3substituents selected from alkyl group having 1 to 4 carbon atoms, arylgroup having 6 to 14 carbon atoms, hydroxy group, alkoxy group having 1to 4 carbon atoms, aralkyloxy group having 7 to 10 carbon atoms andhalogen atom.

In the formula (I), U is a bond, an oxygen atom, a sulfur atom, —SO— or—SO₂—. U is preferably a bond, an oxygen atom or a sulfur atom, morepreferably a bond or an oxygen atom, particularly preferably a bond.When ring B in the formula (I) is a benzene ring optionally furtherhaving 1 to 3 substituents, U represents a bond. As used herein, thesubstituent is preferably an alkyl group having 1 to 4 carbon atoms, anaryl group having 6 to 14 carbon atoms, a hydroxy group, an alkoxy grouphaving 1 to 4 carbon atoms, an aralkyloxy group having 7 to 10 carbonatoms or a halogen atom.

As the “divalent hydrocarbon group having 1 to 20 carbon atoms”represented by W in the formula (I), those exemplified for theaforementioned Q can be mentioned.

W is preferably C₁₋₆ alkylene or C₂₋₆ alkenylene, more preferably —CH₂—,—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH═CH— and the like. Particularly, —CH₂—is preferable.

In the formula (I), R³ is —OR⁸ (R⁸ is a hydrogen atom or an optionallysubstituted hydrocarbon group) or —NR⁹R¹⁰ (R⁹ and R¹⁰ are the same ordifferent and each is a hydrogen atom, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group or anoptionally substituted acyl group, or R⁹ and R¹⁰ may be bonded to forman optionally substituted ring).

As the “optionally substituted hydrocarbon group” represented by R⁸, the“optionally substituted hydrocarbon group” exemplified for theaforementioned R¹³ and R¹⁴ can be mentioned.

The “optionally substituted hydrocarbon group” is preferably “alkylgroup having 1 to 4 carbon atoms”, “C₆₋₁₀ aryl group optionally having 1to 3 substituents selected from alkyl group having 1 to 4 carbon atomsand halogen atom (e.g., fluorine, chlorine, bromine, iodine)”, and thelike.

As used herein, as the “alkyl group having 1 to 4 carbon atoms”, forexample, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, t-butyl andthe like can be mentioned. Particularly, methyl and ethyl arepreferable. As the “halogen atom”, chlorine is preferable. As the “C₆₋₁₀aryl group”, phenyl and naphthyl can be mentioned. Particularly, phenylis preferable.

As the “optionally substituted hydrocarbon group” and “optionallysubstituted heterocyclic group” represented by R⁹ and R¹⁰, thoseexemplified for R¹³ and R¹⁴ can be mentioned.

As the “optionally substituted acyl group” represented by R⁹ and R¹⁰,the “optionally substituted acyl group” exemplified as the substituentfor R¹ can be mentioned.

As the ring of the “optionally substituted ring” formed by R⁹ and R¹⁰bonded to each other, for example, a 5- to 7-membered cyclic aminogroup, preferably 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl,4-morpholino, 4-thiomorpholino, 1-piperazinyl and the like can bementioned. As the substituent of the “optionally substituted ring”,those exemplified as the substituent for the aforementioned “optionallysubstituted alicyclic hydrocarbon group” and the like can be mentioned.The number of substituent is, for example, 1 to 3.

R³ is preferably —OR⁸ (the symbol is as defined above), and R⁸ ispreferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.R³ is particularly preferably —OH.

Preferable examples of the compound represented by the formula (I)include the following compound.

A compound wherein R¹ is an oxazolyl, a thiazolyl, a pyrazolyl or atriazolyl, each of which optionally has 1 to 3 substituents selectedfrom

-   1) a C₁₋₁₀ alkyl group optionally having 1 to 3 substituents    selected from a C₁₋₆ alkoxy group optionally substituted by 1 to 3    halogen atoms, a halogen atom, a nitro group, a hydroxy group and an    amino group;-   2) a C₃₋₁₀ cycloalkyl group optionally having 1 to 3 substituents    selected from a C₁₋₆ alkyl group optionally substituted by 1 to 3    halogen atoms, a C₁₋₆ alkoxy group optionally substituted by 1 to 3    halogen atoms, a halogen atom, a nitro group, a hydroxy group and an    amino group;-   3) an aromatic heterocyclic group (preferably furyl, thienyl,    pyridyl, pyrazinyl etc.) optionally having 1 to 3 substituents    selected from a C₁₋₆ alkyl group optionally substituted by 1 to 3    halogen atoms, a C₁₋₆ alkoxy group optionally substituted by 1 to 3    halogen atoms, a halogen atom, a nitro group, a hydroxy group and an    amino group; and-   4) a C₆₋₁₄ aromatic hydrocarbon group (preferably, phenyl, naphthyl    etc.) optionally having 1 to 3 substituents selected from a C₁₋₆    alkyl group optionally substituted by 1 to 3 halogen atoms, a C₁₋₆    alkoxy group optionally substituted by 1 to 3 halogen atoms, a    halogen atom, a nitro group, a hydroxy group and an amino group;-   X is a bond or —NR⁶—, wherein R⁶ is a hydrogen atom or an alkyl    group having 1 to 4 carbon atoms;-   Q is a C₁₋₆ alkylene or a C₂₋₆ alkenylene;-   Y is a bond, an oxygen atom or —NR⁷—, wherein R⁷ is an    amino-protecting group (preferably C₁₋₆ alkoxy carbonyl etc.) (Y is    preferably a bond or an oxygen atom);-   ring A is a benzene ring, a fused aromatic hydrocarbon ring having 9    to 14 carbon atoms (preferably naphthalene etc.), or a 5- or    6-membered aromatic heterocycle (preferably pyridine, oxazole,    isoxazole, thiazole, oxadiazole etc.), each of which optionally    further has 1 to 3 substituents selected from an alkyl group having    1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4    carbon atoms, an aralkyloxy group having 7 to 10 carbon atoms and a    halogen atom;-   Z is —(CH₂)_(n)-Z¹- or -Z¹-(CH₂)_(n)— wherein n is an integer of 1    to 3 and Z¹ is a oxygen atom or a sulfur atom;-   ring B is a pyridine ring or a naphthalene ring, each of which    optionally further has 1 to 3 substituents selected from an alkyl    group having 1 to 4 carbon atoms, an aryl group having 6 to 14    carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon    atoms, an aralkyloxy group having 7 to 10 carbon atoms and a halogen    atom;-   U is a bond or an oxygen atom;-   W is a C₁₋₆ alkylene or a C₂₋₆ alkenylene; and-   R³ is —OR⁸ wherein R⁸ is a hydrogen atom or an alkyl group having 1    to 4 carbon atoms.

Particularly preferable examples of the compound represented by theformula (I) include the following compounds:

-   2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic    acid;-   2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetic    acid;-   2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]acetic    acid;-   2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]phenyl]acetic    acid; and-   2-[2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]acetic    acid.

The salt of a compound of the formula (I) (hereinafter also to bereferred to as Compound (I)) is preferably a pharmacologicallyacceptable salt, and is exemplified by salts with inorganic bases, saltswith organic bases, salts with inorganic acids, salts with organicacids, and salts with basic or acidic amino acids, and the like.

Preferred examples of the salts with inorganic bases, include alkalimetal salts such as sodium salts, potassium salts and the like; alkalineearth metal salts such as calcium salts, magnesium salts and the like;aluminum salts, ammonium salts, and the like.

Preferred examples of the salts with organic bases include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine, etc.

Preferred examples of the salts with inorganic acids include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc.

Preferred examples of the salts with organic acids include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc.

Preferred examples of the salts with basic amino acids include saltswith arginine, lysine, ornithine, etc.

Preferred examples of the salts with acidic amino acids include saltswith aspartic acid, glutamic acid, etc.

Of the aforementioned salts, sodium salts, potassium salts,hydrochlorides, etc. are preferred.

A prodrug of Compound (I) refers to a compound capable of beingconverted to Compound (I) by reactions with an enzyme, gastric juice, orthe like, under physiological conditions in vivo, specifically acompound capable of being converted to Compound (I) upon enzymaticoxidation, reduction, hydrolysis, or the like, or a compound capable ofbeing converted to Compound (I) upon hydrolysis or the like by gastricjuice or the like. Examples of the prodrugs of Compound (I) includecompounds derived by acylation, alkylation or phosphorylation of theamino group of Compound (I) (e.g., compounds derived by eicosanoylation,alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, tetrahydropyranylation, pyrrolidylmethylation,pivaloyloxymethylation or tert-butylation of the amino group of Compound(I), etc.); compounds derived by acylation, alkylation, phosphorylationor boration of the hydroxy group of Compound (I) (e.g., compoundsderived by acetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation or tetrahydropyranylation of thehydroxy group of Compound (I), etc.); and compounds derived byesterification or amidation of the carboxyl group of Compound (I) (e.g.,compounds derived by ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification ormethylamidation of the carboxyl group of Compound (I), etc.), etc. Thesecompounds can be produced from Compound (I) by per se known methods.

The prodrug of Compound (I) may be one capable of being converted toCompound (II) under physiological conditions, as described in “IyakuhinNo Kaihatsu (Development of Drugs)”, vol. 7, Molecular Designing,published by Hirokawa Shoten, 1990, pages 163-198.

In addition, Compound (I) may be labeled with an isotope (e.g. ³H, ¹⁴C,³⁵S, ¹²⁵I, etc.) and the like.

Furthermore, Compound (I) may be anhydrides or hydrates.

Compounds (I) and salts thereof (hereinafter also simply referred to as“compound of the present invention”) are of low toxicity and can be usedas a prophylactic or therapeutic agent of the various diseases mentionedbelow in mammals (e.g., humans, mice, rats, rabbits, dogs, cats,bovines, horses, swine, monkeys, etc.), as such or in the form ofpharmaceutical compositions prepared by admixing with apharmacologically acceptable carrier, etc.

Here, the pharmacologically acceptable carriers are exemplified byvarious organic or inorganic carrier substances in common use asmaterials for pharmaceutical preparations, and they are formulated asexcipients, lubricants, binders, and disintegrants for solidpreparations; and as solvents, solubilizers, suspending agents,isotonizing agents, buffers, soothing agents for liquid preparations,etc. In addition, other additives for pharmaceutical preparations, suchas antiseptics, antioxidants, coloring agents, sweetening agents and thelike, may also be used as necessary.

Preferred examples of the excipients include lactose saccharose,D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystallinecellulose, low substituted hydroxypropylcellulose,carboxymethylcellulose sodium, gum arabic, dextrin pullulan, lightsilcic anhydride, synthetic aluminum silicate, magnesium metasilicatealuminate and the like.

Preferred examples of the lubricants include magnesium stearate, calciumstearate, talc, colloidal silica and the like.

Preferred examples of the binders include gelatinized starch, sucrose,gelatin, gum arabic, methylcellulose, carboxymethylcellulose,carboxymethylcellulose sodium, crystalline cellulose, saccharose,D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.

Preferred examples of the disintegrants include lactose, saccharose,starch, carboxymethylcellulose, carboxymethylcellulose calcium,croscarmellose sodium, carboxymethyl starch sodium, light silicicanhydride, low-substituted hydroxypropylcellulose and the like.

Preferred examples of the solvents include water for injection,physiological saline, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil andthe like.

Preferred examples of the solubilizers include polyethylene glycol,propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, sodium salicylate, sodium acetate and the like.

Preferred examples of the suspending agents include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylamino propionate,lecithin, benzalkonium chloride, benzethonium chloride, monostearicglycerol and the like; hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcelluloseand the like; polysorbates; polyoxyethylene hydrogenated castor oil andthe like.

Preferred examples of the isotonizing agents include sodium chloride,glycerol, D-mannitol, D-sorbitol, glucose and the like.

Preferred examples of the buffers include buffer solutions ofphosphates, acetates, carbonates, citrates and the like, etc.

Preferred examples of the soothing agents include benzyl alcohol and thelike.

Preferred examples of the antiseptics include p-oxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Preferred examples of the antioxidants include sulfites, ascorbates andthe like.

Preferred examples of the coloring agents include food colors such aswater soluble tar colors for food (e.g., Food Color Red Nos. 2 and 3,Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2, etc.),water insoluble lake colors (e.g., aluminum salts of the aforementionedwater soluble tar colors for food, etc.), natural colors (e.g.,β-carotene, chlorophyll, red oxide, etc.) and the like.

Preferred examples of the sweetening agents include saccharin sodium,dipotassium glycyrrhetinate, aspartame, stevia and the like.

Examples of the dosage forms of the above pharmaceutical compositioninclude oral preparations such as tablets, capsules (including softcapsules and microcapsules), granules, powders, syrups, emulsions,suspensions and the like; and parenteral preparations such as injections(e.g., subcutaneous injections, intravenous injections, intramuscularinjections, intraperitoneal injections, etc.), external preparations(e.g., preparations for nasal administration, dermal preparations,ointments, etc.), suppositories (e.g., rectal suppositories, vaginalsuppositories, etc.), pellets, drip infusions, sustained-releasepreparations (e.g., sustained-release microcapsules, etc.), eye dropsand the like. These preparations can each be safely administered, orallyor parenterally.

The pharmaceutical composition can be prepared by conventional methodsin the fields of pharmaceutical manufacturing techniques, for example,methods described in the Japanese Pharmacopoeia, and the like. Specificproduction methods for such preparations are hereinafter described indetail.

An oral preparation, for instance, is produced by adding to the activeingredient, for example, an excipient (e.g., lactose, saccharose,starch, D-mannitol, etc.), a disintegrant (e.g., carboxymethylcellulosecalcium, etc.), a binder (e.g., gelatinized starch, gum arabic,carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone,etc.), a lubricant (e.g., talc, magnesium stearate, polyethyleneglycol6000, etc.), and the like, compression molding the obtained mixture,then, if necessary coating by a method known per se using a coating basefor the purpose of taste masking, enteric coating or sustained release.

Examples of the coating base include a sugar coating base, awater-soluble film coating base, an enteric film coating base, asustained-release film coating base and the like.

As the sugar coating base, saccharose is employed. Further, one or twoor more species selected from talc, precipitated calcium carbonate,gelatin, gum arabic, pullulan, carnauba wax and the like may be used incombination.

Examples of the water-soluble film coating base include cellulosepolymers such as hydroxypropylcellullose, hydroxypropylmethylcellulose,hydroxyethylcellulose, methylhydroxyethylcellulose and the like;synthetic polymers such as polyvinylacetal diethylaminoacetate,aminoalky methacrylate copolymer E [Eudragit E (trademark), RohmPharma], polyvinylpyrrolidone and the like; polysaccharides such aspullulan and the like, and the like.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, cellulose acetate phthalate and the like;acrylic acid polymers such as methacrylic acid copolymer L[Eudragit L(trademark), Rohm Pharma], methacrylic acid copolymer LD [EudragitL-30D55 (trademark), Rohm Pharma], methacrylic acid copolymer S[Eudragit S (trademark), Rohm Pharma] and the like; natural productssuch as shellac and the like, and the like.

Examples of the sustained-release film coating base include cellulosepolymers such as ethylcellulose and the like; acrylic acid polymers suchas aminoalkyl methacrylate copolymer RS [Eudragit RS (trademark), RohmPharma], an ethyl acrylate-methyl methacrylate copolymer suspension[Eudragit NE (trademark), Rohm Pharma] and the like, and the like.

Two or more of the above coating bases may be used in admixture in anappropriate ratio. On the occasion of coating, a shading agent such astitanium oxide, red ferric oxide and the like may be used.

Injections are produced by dissolving, suspending or emulsifying theactive ingredient in an aqueous solvent (e.g. distilled water,physiological saline, Ringer's solution, etc.) or an oleaginous solvent(e.g., vegetable oils such as olive oil, sesame oil, cotton seed oil,corn oil; propylene glycol, etc.) and the like, together with adispersant (e.g. polysorbate 80, polyoxyethylene hydrogenated castor oil60, etc.), polyethylene glycol, carboxymethylcellulose, sodium alginate,etc.), a preservative (e.g. methylparaben, propylparaben, benzylalcohol, chlorobutanol, phenol, etc.), an isotonizing agent (e.g. sodiumchloride, glycerol, D-mannitol, D-sorbitol, glucose, etc.) and the like.If desired, additives such as a solubilizer (e.g. sodium salicylate,sodium acetate, etc.), a stabilizer (e.g. human serum albumin, etc.), asoothing agent (e.g. benzyl alcohol, etc.) and the like, may be used.

The compound of the present invention can be used as an insulinsensitizer, an insulin sensitivity enhancing agent, a retinoid-relatedreceptor function regulating agent, a ligand for peroxisomeproliferator-activated receptors, and a ligand for retinoid X receptor,etc. The term “function regulating agent” used here stands for both anagonist and an antagonist.

The compound of the present invention has a hypoglycemic action, ahypolipidemic action, a hypoinsulinemic action, an insulin resistanceimproving action, an insulin sensitivity enhancing action, and aretinoid-related receptor function regulating activity. The functionregulating agent may be a partial agonist or a partial antagonist.

The term “retinoid-related receptor” used here is classified as nuclearreceptors, and is a DNA-binding transcription factor whose ligand is asignal molecule such as oil-soluble vitamins, etc., and may be any of amonomer receptor, a homodimer receptor and a heterodimer receptor.

Here, examples of the monomer receptor include retinoid O receptor(hereinafter, also abbreviated as ROR) α (GenBank Accession No. L14611),RORβ (GenBank Accession No.L14160), RORγ (GenBank Accession No. U16997);Rev-erb α (GenBank Accession No. M24898), Rev-erb β (GenBank AccessionNo. L31785); ERRα (GenBank Accession No. X51416), ERRβ (GenBankAccession No. X51417); Ftz-FI α (GenBank Accession No. S65876), Ftz-FI β(GenBank Accession No. M81385); TIx (GenBank Accession No. S77482); GCNF(GenBank Accession No. U14666) and the like.

Examples of the homodimer receptor include homodimers formed by retinoidX receptor (hereinafter, also abbreviated as RXR) α (GenBank AccessionNo. X52773), RXRβ (GenBank Accession No. M84820), RXRγ (GenBankAccession No. U38480); COUPα (GenBank Accession No. X12795), COUPβ(GenBank Accession No. M64497) COUPγ (GenBank Accession No. X12794);TR2α (GenBank Accession No. M29960), TR2α (GenBank Accession No.L27586); or HNF4α (GenBank Accession No. X76930), HNF4γ (GenBankAccession No. Z49826), etc.

Examples of the heterodimer receptor include heterodimers which areformed by the above-mentioned retinoid X receptor (RXRα, RXRβ or RXRγ)and one receptor selected from retinoid A receptor (hereinafter, alsoabbreviated as RAR) α (GenBank Accession No. X06614), RARβ (GenBankAccession No. Y00291), RARγ (GenBank Accession No. M24857); thyroidhormone receptor (hereinafter, also abbreviated as TR) α (GenBankAccession No. M24748), TRβ (GenBank Accession No. M26747); vitamin Dreceptor (VDR) (GenBank Accession No. JO3258): peroxisomeproliferator-activated receptor (hereinafter, also abbreviated as PPAR)α (GenBank Accession No. L02932), PPARβ (PPAR δ) (GenBank Accession No.U10375), PPARγ (GenBank Accession No. L40904); LXRα (GenBank AccessionNo. U22662); LXRβ (GenBank Accession No. U14534); FXR (GenBank AccessionNo. U18374); MB67 (GenBank Accession No. L29263); ONR (GenBank AccessionNo. X75163); NURα (GenBank Accession No. L13740), NURβ (GenBankAccession No. X75918) and NURγ (GenBank Accession No. U12767).

The compound of the present invention has an excellent ligand activityparticularly to retinoid X receptors (RXRα, RXRβ, RXRγ) and toperoxisome proliferator-activated receptors (PPARα, PPARβ (PPARδ),PPARγ) among the above-mentioned retinoid-related receptors.

Further, the compound of the present invention has an excellent ligandactivity to peroxisome proliferator-activated receptors in heterodimerreceptors formed from a retinoid X receptor and a peroxisomeproliferator-activated receptor, and preferably in heterodimer receptorsformed from RXRα and PPARγ.

Accordingly, the retinoid-related receptor ligand of the presentinvention can be used advantageously as a ligand for peroxisomeproliferator-activated receptors or a ligand for retinoid X receptors.

The compound of the present invention can be used as, for example, aprophylactic or therapeutic agent of diabetes mellitus (e.g., type 1diabetes mellitus, type 2 diabetes mellitus, gestational diabetesmellitus, etc.); a prophylactic or therapeutic agent of hyperlipidemia(e.g., hypertriglyceridemia, hypercholesterolemia,hypo-high-density-lipoproteinemia, postprandial hyperlipidemia, etc.);an insulin sensitizer; an insulin sensitivity enhancing agent; aprophylactic or therapeutic agent of impaired glucose tolerance (IGT);and an agent for preventing progress from impaired glucose tolerance todiabetes mellitus.

Regarding diagnostic criteria of diabetes mellitus, new diagnosticcriteria were reported by the Japan Diabetes Society in 1999.

According to this report, diabetes mellitus is a condition wherein thefasting blood glucose level (glucose concentration in venous plasma) isnot less than 126 mg/dl, the 2-hour value (glucose concentration invenous plasma) of the 75 g oral glucose tolerance test (75 g OGTT) isnot less than 200 mg/dl, or the non-fasting blood glucose level (glucoseconcentration in venous plasma) is not less than 200 mg/dl. In addition,a condition which does not fall within the scope of the above definitionof diabetes mellitus, and which is not a “condition wherein the fastingblood glucose level (glucose concentration in venous plasma) is lessthan 110 mg/dl or the 2-hour value (glucose concentration in venousplasma) of the 75 g oral glucose tolerance test (75 g OGTT) is less than140 mg/dl” (normal type), is called the “borderline type”.

In addition, regarding diagnostic criteria for diabetes mellitus, newdiagnostic criteria were reported by ADA (American Diabetes Association)in 1997 and by WHO in 1998.

According to these reports, diabetes mellitus is a condition wherein thefasting blood glucose level (glucose concentration in venous plasma) isnot less than 126 mg/dl, and the 2-hour value (glucose concentration invenous plasma) of the 75 g oral glucose tolerance test is not less than200 mg/dl

In addition, according to the above reports, impaired glucose toleranceis a condition wherein the fasting blood glucose level (glucoseconcentration in venous plasma) is less than 126 mg/dl, and the 2-hourvalue (glucose concentration in venous plasma) of the 75 g oral glucosetolerance test is not less than 1400 mg/dl and less than 200 mg/dl.Furthermore, according to the ADA report, a condition wherein thefasting blood glucose level (glucose concentration in venous plasma) isnot less than 110 mg/dl and less than 126 mg/dl, is called IFG (impairedfasting glucose). On the other hand, according to the WHO report, acondition of IFG (impaired fasting glucose) as such wherein the 2-hourvalue (glucose concentration in venous plasma) of the 0.75 g oralglucose tolerance test is less than 140 mg/dl, is called IFG (impairedfasting glycemia).

The compound of the present invention can also be used as a prophylacticor therapeutic agent of diabetes mellitus, borderline type, impairedglucose tolerance, IFG (impaired fasting glucose) and IFG (impairedfasting glycemia) as defined by the above new diagnostic criteria.Furthermore, the compound of the present invention can also be used toprevent progress from the borderline type, impaired glucose tolerance,IFG (impaired fasting glucose) or IFG (impaired fasting glycemia) todiabetes mellitus.

The compound of the present invention can be used also as a prophylacticor therapeutic agent of, for example, diabetic complications (e.g.,neuropathy, nephropathy, retinopathy, cataract, macroangiopathy,osteopenia, diabetic hyperosmolar coma, infectious diseases (e.g.,respiratory infection, urinary tract infection, gastrointestinal tractinfection, dermal soft tissue infection, inferior limb infection, etc.),diabetic gangrene, xerostomia, lowered sense of hearing, cerebrovasculardisease, peripheral circulatory disturbance, etc.), obesity,osteoporosis, cachexia (e.g., carcinomatous cachexia, tuberculouscachexia, diabetic cachexia, hemopathic cachexia, endocrinopathiccachexia, infectious cachexia, cachexia induced by acquiredimmunodeficiency syndrome), fatty liver, hypertension, polycystic ovarysyndrome, renal diseases (e.g., diabetic nephropathy, glomerularnephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis, terminal renal disease, etc.), muscular dystrophy,myocardiac infarction, angina pectoris, cerebrovascular disease (e.g.,cerebral infarction, cerebral apoplexy), insulin resistant syndrome,syndrome X, hyperinsulinemia, hyperinsulinemia-induced sensory disorder,tumor (e.g., leukemia, breast cancer, prostate cancer, skin cancer,etc.), irritable intestinal syndrome, acute or chronic diarrhea,inflammatory diseases (e.g., chronic rheumatoid arthritis, spondylitisdeformans, osteoarthritis, lumbago, gout, postoperative or traumaticinflammation, remission of swelling, neuralgia, pharyngolaryngitis,cystitis, hepatitis (including non-alcoholic steatohepatitis),pneumonia, pancreatitis, inflammatory colonic disease, ulcerativecolitis, etc.), visceral obesity syndrome, etc.

The compound of the present invention possess a total cholesterollowering action and enhance a plasma anti-arteriosclerosis index [(HDLcholesterol/total cholesterol)×100], and therefore, can be used as aprophylactic or therapeutic agent of arteriosclerosis (e.g.,atherosclerosis, etc.) and the like.

Also, the compound of the present invention can be used for amelioratingconditions such as bellyache, nausea, vomiting, dysphoria inepigastrium, and the like, each of which is accompanied bygastrointestinal ulcer, acute or chronic gastritis, biliary dyskinesia,or cholecystitis, etc., and the like.

Further, the compound of the present invention can control (enhance orinhibit) appetite and food intake, and therefore, can be used, forexample, as an agent for treating leanness and cibophobia (the weightincrease in administration subjects suffering from leanness orcibophobia) or as an agent for treating obesity.

The compound of the present invention can be also used as a prophylacticor therapeutic agent of TNF-α mediated inflammatory diseases. The TNF-αmediated inflammatory diseases mean inflammatory diseases which occur inthe presence of TNF-α and can be treated by way of a TNF-α inhibitoryaction. Examples of such inflammatory diseases include diabeticcomplications (e.g., retinopathy, nephropathy, neuropathy,macroangiopathy, etc.), rheumatoid arthritis, spondylitis deformans,osteoarthritis, lumbago, gout, postoperative or traumatic inflammation,remission of swelling, neuralgia, pharyngolaryngitis, cystitis,hepatitis, pneumonia, gastric mucosal injury (including aspirin-inducedgastric mucosal injury), etc.

The compound of the present invention have an apoptosis inhibitoryactivity, and can be used as a prophylactic or therapeutic agent ofdiseases mediated by promotion of apoptosis. Examples of the diseasesmediated by promotion of apoptosis include viral diseases (e.g., AIDS,fulminant hepatitis, etc.) neurodegenerative diseases (e.g., Alzheimersdisease, Parkinson's disease, amyotropic lateral sclerosis, retinitispigmentosa, cerebellar degeneration, etc.), myelodysplasia (e.g.,aplastic anemia, etc.), ischemic diseases. (e.g., myocardial infarction,cerebral apoplexy, etc.), hepatic diseases (e.g., alcoholic hepatitis,hepatitis B, hepatitis C, etc.), joint-diseases (e.g., osteoarthritis,etc.), atherosclerosis, etc.

Also, the compound of the present invention can be used for reducingvisceral fats, inhibiting accumulation of visceral fats, amelioratingglycometabolism, ameliorating lipidmetabolism, ameliorating insulinresistance, inhibiting production of oxidized LDL, amelioratinglipoprotein metabolism, ameliorating coronary artery metabolism,preventing or treating cardiovascular complications, preventing ortreating heart failure complications, lowering blood remnant, preventingor treating anovulation, preventing or treating hirsutism, preventing ortreating hyperandrogenism, etc.

Also, the compound of the present invention can be used, for secondaryprevention and for inhibition in progress, of the various diseasesdescribed above (e.g., cardiovascular events such as myocardialinfarction, etc.).

The compound of the present invention can be used in combination withmidazolam, ketoconazole, etc.

Although the doses of the compound of the present invention varydepending on administration subject, administration route, targetdisease, clinical condition, etc., the compound of the present inventionis administered at a usual dosage per administration of about 0.005 to50 mg/kg body weight, preferably 0.01 to 2 mg/kg body weight, morepreferably 0.025 to 0.5 mg/kg body weight, for oral administration to anadult diabetic patient, for instance. These doses are preferablyadministered 1 to 3 times a day.

The compound of the present invention can be used in combination with adrug such as a therapeutic agent for diabetes mellitus, a therapeuticagent for diabetic complications, an antihyperlipidemic agent, ahypotensive agent, an antiobesity agent, a diuretic agent, achemotherapeutic agent, an immunotherapeutic agent and the like(hereinafter, abbreviated as a concomitant drug). The concomitant drugmay be a low molecular weight compound, or a high molecular protein,polypeptide, antibody, or vaccine and the like. On such occasions, thetiming of administration of the compound of the present invention andthat of the concomitant drug is not limited. They may be administeredsimultaneously or at staggered times to the administration subject. Thedose of the concomitant drug can be appropriately selected based on thedose which is clinically employed. The proportion of the compound of thepresent invention and the concomitant drug can be appropriately selectedaccording to the administration subject, administration route, targetdisease, clinical condition, combination, and other factors. In caseswhere the administration subject is human, for instance, the concomitantdrug may be used in an amount of 0.01 to 100 parts by weight per part byweight of the compound of the present invention.

Examples of the therapeutic agent for diabetes mellitus include insulinpreparations (e.g., animal insulin preparations extracted from thebovine or swine pancreas; human insulin preparations synthesized by agenetic engineering technique using Escherichia coli or a yeast; insulinzinc; insulin zinc protamine; insulin fragment or derivative thereof(e.g., INS-1 etc.) etc.), insulin sensitizers (e.g., pioglitazonehydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570,JTT-501, MCC-555, YM-440, KRP-297, CS-011, FK-614, etc.), α-glucosidaseinhibitors (e.g., voglibose, acarbose, miglitol, emiglitate, etc.),biguamides (e.g., phenformin, metformin, buformin, etc.), insulinsecretagogues [sulfonylureas (e.g., tolbutamide, glibenclamide,gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide,glimepiride, glipizide, glybuzole, etc.), repaglinide, nateglinide,mitiglinide or its calcium salt hydrate, GLP-1, etc.],dipeptidylpeptidase IV inhibitors (e.g., NVP-DPP-278, PT-100, etc.), β3agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677,BMS-196085, AZ-40140, etc.), amyrin agonist (e.g., pramlintide, etc.),phosphotyrosine phosphatase inhibitors (e.g., vanadic acid, etc.),gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors,glucose-6-phosphatase inhibitors, glucagon antagonists, etc.), SGLUT(sodium-glucose cotransporter) inhibitors (e.g. T-1095, etc.), and thelike.

Examples of the therapeutic agent for diabetic complications includealdose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat,zopolrestat, minalrestat, fidarestat (SNK-860), CT-112, etc.),neurotrophic factors (e.g., NGF, NT-3, BDNF, etc.), production andsecretion promoters of neurotrophic factors, PKC inhibitors (e.g.,LY-333531, etc.), AGE inhibitors (e.g., ALT946, pimagedine,pyratoxathine, N-phenacylthiazolium bromide (ALT766), EXO-226, etc.),active oxygen scavengers (e.g. thioctic acid, etc.), cerebralvasodilators (e.g., tiapuride, mexiletine, etc.).

Examples of the antihyperlipidemic agent include statin compounds whichare cholesterol synthesis inhibitors (e.g., cerivastatin, pravastatin,simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or theirsalts (e.g., sodium salt, etc.), etc.), squalene synthase inhibitors orfibrate compounds (e.g., bezafibrate, clofibrate, simfibrate,clinofibrate, etc.) having a triglyceride lowering action, and the like.

Examples of the hypotensive agent include angiotensin converting enzymeinhibitors (e.g., captopril, enalapril, delapril, etc.), angiotensin IIantagonists (e.g., candesartan cilexetil, losartan, eprosartan,valsartan, termisartan, irbesartan, tasosartan, etc.), calciumantagonist (e.g., manidipine, nifedipine, nicardipine, amlodipine,efonidipine, etc.), clonidine, and the like.

Examples of the antiobesity agent include antiobesity drugs acting onthe central nervous system (e.g. dexfenfluramine, fenfluramine,phentermine, sibutramine, anfepramon, dexamphetamine, mazindol,phenylpropanolamine, clobenzorex, etc.), pancreatic lipase inhibitors(e.g. orlistat, etc.), β3 agonists (e.g. CL-316243, SR-58611-A,UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140, etc.), anorecticpeptides (e.g. leptin, CNTF (Ciliary Neurotrophic Factor), etc.),cholecystokinin agonists (e.g. lintitript, FPL-15849, etc.), and the,like.

Examples of the diuretic agent include xanthine derivatives (e.g.,theobromine sodium salicylate, theobromine calcium salicylate, etc.),thiazide preparations (e.g., ethiazide, cyclopenthiazide,trichlormethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide,etc.), antialdosterone preparations (e.g., spironolactone, triamterene,etc.), carbonate dehydratase inhibitors (e.g., acetazolamide, etc.),chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mefruside,indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide,bumetamide, furosemide, and the like.

Examples of the chemotherapeutic agent include alkylating agents (e.g.,cyclophosphamide, ifosfamide, etc.), metabolic antagonists (e.g.,methotrexate, 5-fluorouracil, etc.), antitumor antibiotics (e.g.,mitomycin, adriamycin, etc.), plant-derived antitumor agents (e.g.,vincristine, vindesine, Taxol, etc.), cisplatin, carboplatin, etoposide,and the like. Among these, 5-fluorouracil derivatives such as Furtulon,Neo-Furtulon and the like are preferable.

Examples of the immunotherapeutic agent include microorganism- orbacterium-derived components (e.g., muramyl dipeptide derivatives,Picibanil, etc.), immunopotentiator polysaccharides (e.g., lentinan,schizophyllan, krestin, etc.), genetically engineered cytokines (e.g.,interferons, interleukins (IL), etc.), colony stimulating agents (e.g.,granulocyte colony stimulating factor, erythropoietin, etc.), and thelike. Among these, IL-1, IL-2, IL-12 and the like are preferable.

As the concomitant drug, moreover, agents whose effects of amelioratingcachexia have been confirmed in animal models or clinically, namelycyclooxygenase inhibitors (e.g., indomethacin, etc.). (Cancer Research,vol. 49, pp. 5935-5939, 1989), progesterone derivatives (e.g., megestrolacetate) (Journal of Clinical Oncology, vol. 12, pp. 213-225, 1994),glucocorticoids (e.g. dexamethasone, etc.), metoclopramidepharmaceuticals, tetrahydrocannabinol pharmaceuticals (the abovereferences are applied to both), fat metabolism ameliorating agents(e.g., eicosapentanoic acid, etc.) (British Journal of Cancer, vol. 68,pp 314-318, 1993), growth hormones, IGF-1, and antibodies to thecachexia-inducing factor TNF-α, LIF, IL-6 or oncostatin M, and the likecan also be mentioned.

As the concomitant drug, moreover, neuranagenesis promoter (e.g., Y-128,VX-853, prosaptide, etc.), antidepressant (e.g., desipramine,amitriptyline, imipramine, etc.), antiepileptic (e.g., lamotrigine,etc.), antiarrhythmic (e.g., mexiletine, etc.), ligand for acetylcholinereceptor (e.g., ABT-594, etc.), endothelin receptor antagonist (e.g.,ABT-627, etc.), monoamine uptake inhibitor (e.g., tramadole, etc.),anesthetic analgesic (e.g., morphine, etc.), GABA receptor agonist.(e.g., gabapentin, etc.), α2 receptor agonist (e.g., clonidine, etc.),topical analgesic (e.g., capsaicin, etc.), protein kinase C inhibitor(e.g., LY-333531, etc.), antianxiety drugs (e.g., benzodiazepine, etc.),phosphodiesterase inhibitor (e.g., sildenafil citrate, etc.), dopamineagonist (e.g., apomorphine, etc.), the therapeutic agent forosteoporosis (e.g., alfacalcidol, calcitriol, elcaltonin, calcitoninsalmon, estriol, ipriflavone, pamidronate disodium, alendronate sodiumhydrate, incadronate disodium, etc.), the antidementia agent (e.g.,tacrine, donepezil, rivastigmine, galantamine, etc.), the therapeuticagent for incontinentia or pollakiuria (e.g., flavoxate hydrochloride,oxybutynin hydrochloride, propiverine hydrochloride, etc.), and the likecan be mentioned.

The concomitant drug is preferably an insulin preparation, an insulinsensitizer, an α-glucosidase inhibitor, a biguamide, an insulinsecretagogue (preferably sulfonylurea), etc.

The above concomitant drugs can be used in combination of two or morespecies in an appropriate ratio. In the case of using two or moreconcomitant drugs, for example, preferable combinations include thefollowings.

1) an insulin sensitizer and an insulin preparation;

2) an insulin sensitizer and an insulin secretagogue;

3) an insulin sensitizer and an α-glucosidase inhibitor;

4) an insulin sensitizer and a biguanide;

5) an insulin sensitizer, an insulin preparation and a biguanide;

6) an insulin sensitizer, an insulin preparation and an insulinsecretagogue;

7) an insulin sensitizer, an insulin preparation and an α-glucosidaseinhibitor;

8) an insulin sensitizer, an insulin secretagogue and a biguanide;

9) an insulin sensitizer, an insulin secretagogue and an α-glucosidaseinhibitor; and

10) an insulin sensitizer, a biguanide and an α-glucosidase inhibitor.

When the compound of the present invention is used in combination with aconcomitant drug, the amount of each drug can be reduced within a saferange by taking their adverse effects into consideration. Particularly,the dose of an insulin sensitizer, an insulin secretagogue and abiguamide can be reduced as compared with the normal dose. Accordingly,an adverse effect which may be caused by these agents can be safelyprevented. In addition, the dose of an agent for diabetic complications,an anti-hyperlipidemic agent and a hypotensive agent can be reducedwhereby an adverse effect which may be caused by these agents can beeffectively prevented.

In the following, the production method of the compound of the presentinvention is explained.

The compound of the present invention can be produced by a method knownperuse, such as the following Method A to Method J or a method analogousthereto. In each of the following production methods, the startingcompound may be used as a salt, and as such salt, those exemplified asthe salt of the aforementioned Compound (I) can be used.

The compound (I-1) of the formula (I) wherein Z is —(CH₂)n-Z²-(n is asdefined above and Z² is an oxygen atom, a sulfur atom or —NR¹⁶— (R¹⁶ isas defined above)) can be produced by, for example, the following MethodA.

wherein L is a leaving group and other symbols are as defined above.

As the leaving group represented by L, for example, hydroxy group,halogen atom, —OSOR¹⁵ (R¹⁵ is an alkyl group having 1 to 4 carbon atoms,or aryl group having 6 to 10 carbon atoms which may be substituted by analkyl group having 1 to 4 carbon atoms and the like can be mentioned.

Here, the alkyl group having 1 to 4 carbon atoms in the “alkyl grouphaving 1 to 4 carbon atoms” and “aryl group having 6 to 10 carbon atomswhich may be substituted by an alkyl group having 1 to 4 carbon atoms”for R¹⁵ is exemplified by methyl, ethyl, propyl; isopropyl, butyl,isobutyl, sec-butyl, and t-butyl, with preference given to methyl. Thearyl group having 6 to 10 carbon atoms in the “aryl group having 6 to 10carbon atoms which may be substituted by an alkyl group having 1 to 4carbon atoms” for R¹⁵ is exemplified by phenyl and naphthyl, withpreference given to phenyl.

In this method Compound (I-1) is produced by a reaction of Compound (II)and Compound (III).

When L is a hydroxy group, this reaction is carried out by a methodknown per se, e.g., the method described in Synthesis, page 1 (1981), ora method analogous thereto. Namely, this reaction is normally carriedout in the presence of an organic phosphorus compound and anelectrophilic agent in a solvent which does not interfere with thereaction.

Examples of the organic phosphorus compound include triphenylphosphine,tributylphosphine and the like.

Examples of the electrophilic agent include diethyl azodicarboxylate,diisopropyl azodicarboxylate, azodicarbonyldipiperazine and the like.

The amount of the organic phosphorus compound and electrophilic agentused is preferably about 1 to about 5 mole equivalents relative toCompound (III).

Examples of the solvent which does not interfere with the reactioninclude ethers such as diethyl ether, tetrahydrofuran, dioxane and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; amides such as N,N-dimethylformamide and the like; and sulfoxidessuch as dimethyl sulfoxide and the like, and the like. These solventsmay be used in a mixture of two or more kinds in appropriate ratios.

The reaction temperature is normally about −50 to about 150° C.,preferably about −10 to about 100° C.

The reaction time is normally about 0.5 to about 20 hours.

When L is a halogen atom or —OSO₂R¹⁵, this reaction is carried out by aconventional method in the presence of a base in a solvent which doesnot interfere with the reaction.

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamineN,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;and alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium t-butoxide and the like

The amount of these bases used is preferably about 1 to about 5 moleequivalents relative to Compound (III).

Examples of the solvent which does not interfere with the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; and sulfoxides such asdimethyl sulfoxide and the like, and the like. These solvents may beused in a mixture of two or more kinds in appropriate ratios.

The reaction temperature is normally about −50 to about 150° C.preferably about −10 to about 100° C.

The reaction time is normally about 0.5 to about 20 hours.

Compound (I) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like

Compound (II), which is used as the starting compound in Method A above,can be produced by a method described in, for example, EP-A 710659, EP-A629624 (JP-A 7 (1995)-53555), WO 98/03505 or WO 99/58510, etc., or amethod analogous thereto.

Compound (III) used as the starting compound in the above-mentionedMethod A can be produced according to, for example, a method describedin The Journal of Organic Chemistry, vol. 55, pp. 5867-5877 (1990),Bulletin de la Societe Chimigue de France, pp. 901-904 (1988), ChemicalAbstracts, vol. 94, 174782n, Chemical Abstracts, vol. 95, 186786a andthe like, or a method analogous thereto.

A compound of the formula (I) wherein R³ is OR⁸, U is a bond and W is—CH═CH— or —(CH₂)₂— [Compound (I-2) or (I-3), respectively] can be alsoproduced according to the following

Method B.

wherein each symbol is as defined above.(Process 1)

In this Process, Compound (IV) is subjected to a reduction reaction toproduce Compound (V). This reaction is carried out by a conventionalmethod in the presence of a reducing agent in a solvent which does notinterfere with the reaction.

Examples of the reducing agent include sodium borohydride, lithiumborohydride, lithium aluminum hydride, and diisobutyl aluminum hydrideand the like.

The amount of the reducing agent used is preferably about 0.5 to about10 mole equivalents relative to Compound (IV).

Examples of the solvent which does not interfere with the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; water; and alcohols such as methanol, ethanol, isopropanol and thelike, and the like. These solvents may be used in a mixture of two ormore kinds in appropriate ratios.

The reaction temperature is normally about −50 to about 150° C.,preferably about −10 to about 100° C.

The reaction time is normally about 0.5 to about 20 hours.

Compound (V) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.Alternatively, Compound (V) may be used as a reaction mixture for thenext Process without isolation.

Compound (IV), which is used as the starting compound in Process 1, canbe produced by, for example, Method A above. In addition, Compound (IV)can also be produced by the method described in, for example, Journal ofHeterocyclic Chemistry, vol. 24, p. 1669 (1987); Journal of OrganicChemistry, vol. 62, p. 2649 (1997); Bioorganic & Medicinal ChemistryLetters, vol. 6, p. 1047 (1996), etc., or a method analogous thereto.

(Process 2)

In this Process, Compound (V) is subjected to an oxidation reaction toproduce Compound (VI). This reaction is carried out by a conventionalmethod in the presence of an oxidizing agent in a solvent which does notinterfere with the reaction.

Examples of the oxidizing agent include metal oxidizing agents such asmanganese dioxide, pyridinium chlorochromate, pyridinium dichromate, andruthenium oxide and the like, and the like.

The amount of the oxidizing agent used is preferably about 1 to about 10mole equivalents relative to Compound (V).

Examples of the solvent which does not interfere with the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; and halogenated hydrocarbons such as chloroform, dichloromethaneand the like, and the like. These solvents may be used in a mixture oftwo or more kinds in appropriate ratios.

The reaction temperature is normally about −50 to about 150° C.,preferably about −10 to about 100° C.

The reaction time is normally about 0.5 to about 20 hours.

In addition, Compound (VI) can also be produced by adding a reactionreagent such as sulfur trioxide-pyridine complex or oxalyl chloride andthe like to Compound (V) in dimethyl sulfoxide or a solvent mixture ofdimethyl sulfoxide and a halogenated hydrocarbon (e.g., chloroform,dichloromethane etc.), and then reacting it with an organic base such astriethylamine, N-methylmorpholine and the like.

The amount of the reaction reagent used is preferably about 1 to about10 mole equivalents relative to Compound (V).

The amount of the organic base used is preferably about 1 to about 10mole equivalents relative to Compound (V).

The reaction temperature is normally about −50 to about 150° C.,preferably about −10 to about 100° C. The reaction time is normallyabout 0.5 to about 20 hours.

Compound (VI) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.Alternatively, Compound (VI) may be used as a reaction mixture for thenext Process without isolation.

(Process 3)

In this process, Compound (I-2) is produced by reacting Compound (VI)with an organic phosphorus reagent. This reaction is carried out by aconventional method in the, presence of a base in a solvent which doesnot interfere with the reaction.

Examples of the organic phosphorus reagent include methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate, ethyldimethylphosphonoacetate and the like.

The amount of the organic phosphorus reagent used is preferably about 1to about 10 mole equivalents relative to Compound (VI).

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;and alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium t-butoxide and the like.

The amount of these bases used is preferably about 1 to about 5 moleequivalents relative to Compound (VI).

Examples of the solvent which does not interfere with the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide and the like, and the like. These solventsmay be used in a mixture of two or more kinds in appropriate ratios.

The reaction temperature is normally about −50 to about 150° C.,preferably about −10 to about 100° C.

The reaction time is normally about 0.5 to about 20 hours.

Compound (I-2) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.Alternatively, Compound (I-2) may be used as a reaction mixture for thenext Process without isolation.

(Process 4)

In this Process, Compound (I-2) is subjected to a hydrogenation reactionto produce Compound (I-3). This reaction is carried out by aconventional method under a hydrogen atmosphere or in the presence of aproton source such as formic acid and the like and a metal catalyst, ina solvent which does not interfere with the reaction.

Examples of the metal catalyst include transition metal catalysts suchas palladium-carbon, palladium black, platinum oxide, Raney nickel,Wilkinson's catalyst and the like, and the like.

The amount of these transition metal catalysts used is preferably about0.01 to about 10 mole equivalents relative to Compound (I-2).

Examples of the solvent which does not interfere with the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether, and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; amides such as N,N-dimethylformamide and the like; alcoholssuch as methanol, ethanol, isopropanol and the like, and the like. Thesesolvents may be used in a mixture of two or more kinds in appropriateratios.

The reaction temperature is normally about −50 to about 150° C.,preferably about −10 to about 100° C.

The reaction time is normally about 0.5 to about 20 hours.

Compound (I-3) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.

Compound (I-4) of the formula (I) wherein Y is Y¹ (oxygen atom, sulfuratom or —NR⁷— (R⁷ is as defined above)) can be also produced accordingto, for example, the following Method C.

wherein each symbol is as defined above.

In this method, Compound (I-4) is produced by reacting Compound (VII)with Compound (VIII). This reaction is carried out in the same manner asthe reaction of Compound (II) and Compound (III) in Method A.

Compound (I-4) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.

Compound (VII), which is used as the starting compound in Method Cabove, can be produced by a method described in, for example, Journal ofMedicinal Chemistry, vol. 35, p. 2617 (1992); Chemical andPharmaceutical Bulletin, vol. 34, p. 2840 (1986); WO 98/03505, etc., oran analogous method thereof.

Compound (I-6) of the formula (I) wherein R³ is OH can be also producedaccording to, for example, the following Method D.

wherein the symbols have the same meanings as above.

In this method, Compound (I-6) is produced by subjecting Compound (I-5)to a hydrolysis reaction. This reaction is carried out by a conventionalmethod in the presence of an acid or a base in an aqueous solvent.

Examples of the acid include hydrochloric acid, sulfuric acid, aceticacid, hydrobromic acid and the like.

Examples of the base include alkali metal carbonates such as potassiumcarbonate, sodium carbonate and the like; alkali metal alkoxides such assodium methoxide and the like; and alkali metal hydroxides such aspotassium hydroxide, sodium hydroxide, lithium hydroxide and the like,and the like.

The amount of the acid or base used is normally in excess to Compound(I-5). Preferably, the amount of the acid used is about 2 to about 50equivalents relative to Compound (I-5), and the amount of the base usedis about 1.2 to about 5 equivalents relative to Compound (I-5).

Examples of the aqueous solvents include solvent mixtures of water andone or more solvents selected from alcohols such as methanol, ethanoland the like; ethers such as tetrahydrofuran, dioxane, diethyl ether andthe like; dimethyl sulfoxide, acetone and the like, and the like.

The reaction temperature is normally about −20 to about 150° C.,preferably about −10 to about 100° C.

The reaction time is normally about 0.1 to about 20 hours.

Compound (I-6) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.

Compound (I-5), which is used as the starting compound in Method Dabove, is produced by, for example, Methods A through C above.

For example, Compound (I-7) of the formula (I) wherein R³ is —NR⁹R¹⁰ canalso be produced by Method E below.

wherein the symbols have the same meanings as above.

In this method, Compound (I-7) is produced by subjecting Compound (I-6)to an amidation reaction. This reaction is carried out by a method knownper se, e.g., a method wherein Compound (I-6) and Compound (IX) aredirectly condensed by means of a condensing agent (e.g.,dicyclohexylcarbodiimide, etc.), a method wherein a reactive derivativeof Compound (I-6) and Compound (IX) are reacted as appropriate, or thelike. Here, the reactive derivative of Compound (I-6) is exemplified byacid anhydrides, acid halides (acid chlorides, acid bromides),imidazolides, or mixed acid anhydrides (e.g., anhydrides with methylcarbonate, ethyl carbonate, or isobutyl carbonate, etc.) and the like.

When an acid halide is used, for example, the reaction is carried out inthe presence of a base in a solvent which does not interfere with thereaction.

Examples of the base include triethylamirie, N-methylmorpholine,N,N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate,potassium carbonate and the like.

Examples of the solvent which does not interfere with the reactioninclude halogenated hydrocarbons such as chloroform, dichloromethane andthe like; aromatic hydrocarbons such as benzene, toluene and the like;ethers such as tetrahydrofuran, dioxane, diethyl ether and the like;ethyl acetate, water, and the like. These solvents may be used in amixture of two or more kinds in appropriate ratios.

The amount of Compound (IX) used is 0.1 to 10 mole equivalents,preferably 0.3 to 3 mole equivalents, relative to Compound (I-6).

The reaction temperature is normally −30 to 100° C.

The reaction time is normally 0.5 to 20 hours.

In addition, when a mixed acid anhydride is used, Compound (I-6) and achlorocarbonic acid ester (e.g., methyl chlorocarbonate, ethylchlorocarbonate, isobutyl chlorocarbonate, etc.) are reacted in thepresence of a base (e.g., triethylamine, N-methylmorpholine,N,N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate,potassium carbonate, etc.), and are further reacted with Compound (IX).

The amount of Compound (IX) used is normally 0.1 to 10 mole equivalents,preferably 0.3 to 3 mole equivalents, relative to Compound (I-6).

The reaction temperature is normally −30° C. to 100° C.

The reaction time is normally 0.5 to 20 hours.

Compound (I-7) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.

Compound (I-6), which is used as the starting compound in Method Eabove, is produced, by, for example, Methods A through D above.

Of the Compound (VIII) used as the starting compound in Method C,Compound (VIII-1) wherein Z is —(CH₂)n-Z²-(symbols in the formula are asdefined above) can be produced by, for example, the following Method F.

wherein each symbol is as defined above.

In this method, Compound (VIII-1) is produced by a reacting Compound (X)with Compound (III). This reaction is carried out in the same manner asin the reaction of Compound (II) and Compound (III) in Method A. The—Y¹H moiety of Compound (X) may be protected with a suitable protectinggroup before condensation reaction, and after the reaction, may bedeprotected. As such protecting group, for example, benzyl group,methoxymethyl group or silyl group (trimethylsilyl group,tert-butyldimethylsilyl group etc.) and the like can be mentioned.

Of the Compounds (IV) used as the starting compound in Method B,Compound (IV-1) wherein Z is —(CH₂)n-Z²-(symbols in the formula are asdefined above) can be produced by, for example, the following Method G.

wherein each symbol is as defined above.

In this method, Compound (II) is reacted with Compound (XI) to produceCompound (IV-1). This reaction is carried out in the same manner as inthe reaction of Compound (II) and Compound (III) in Method A.

[Method H]

The aforementioned Compound (I-6) can be also produced by, for example,subjecting a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, tohydrolysis reaction.

Here, the hydrolysis reaction is carried out in the same manner as inthe aforementioned hydrolysis reaction of Compound (I-5).

Of Compound (XII) used as the starting compound in the above-mentionedMethod H, Compound (XIIa) wherein U is a bond and W is —CH₂— can beproduced by, for example, the following Method I.

wherein La is a leaving group and other symbols are as defined above.

As the leaving group represented by La, a halogen atom and —OSOR¹⁵ (R¹⁵is as defined above) exemplified as the aforementioned L can bementioned.

(Process 1)

In this Process, Compound (V) is reacted with a halogenating agent or asulfonylating agent to produce Compound (Va).

As the halogenating agent, for example, hydrochloric acid, thionylchloride, phosphorus tribromide and the like are used. In this case,Compound (Va) wherein La is a halogen (e.g., chlorine, bromine etc.) canbe produced.

The reaction between Compound (V) and a halogenating agent is generallycarried out in a solvent that does not adversely affect the reaction.

As the solvent that does not adversely affect the reaction, for example,halogenated hydrocarbons such as dichloromethane, chloroform; carbontetrachloride and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; ethers such as diethyl ether, diisopropylether, tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethaneand the like; esters such as methyl acetate, ethyl acetate, n-butylacetate, tert-butyl acetate and the like, and the like can be mentioned.These solvents may be used in a mixture of two or more kinds inappropriate ratios. In addition, an excess amount of a halogenatingagent may be used as a solvent.

The amount of the halogenating agent to bemused is generally 1 to 10mole equivalents relative to Compound (V).

The reaction temperature is generally −20 to 100° C.

The reaction time is generally 0.5-24 hrs.

As the sulfonylating agent, for example, methanesulfonyl chloride,benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like can beused. In this case, Compound (Va) wherein La is, for example,methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy and thelike is produced.

The reaction between Compound (V) and a sulfonylating agent is generallycarried out in the presence of a base in a solvent that does notadversely affect the reaction.

As the solvent that does not adversely affect the reaction, for example,halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; ethers such as diethyl ether, diisopropylether, tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethaneand the like; esters such as methyl acetate, ethyl acetate, n-butylacetate, tert-butyl acetate and the like, and the like can be mentioned.These solvents may be used in a mixture of two or more kinds inappropriate ratios.

The amount of the sulfonylating agent to be used is generally 1 to 10mole equivalents relative to Compound (V).

As the base, for example, amines such as triethylamine,N-methylmorpholine and the like; alkali metal salt such as sodiumhydrogencarbonate, potassium hydrogencarbonate, potassium carbonate andthe like, and the like can be mentioned.

The amount of the base to be used is generally 1 to 10 mole equivalentsrelative to Compound (V).

The reaction temperature is generally −20 to 100° C.

The reaction time is generally 0.5-24 hrs.

Compound (Va) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.Alternatively, Compound (Va) may be used as a reaction mixturecontaining Compound (Va) for the next reaction without isolation.

(Process 2)

In this Process, Compound (Va) is reacted with a cyanating agent toproduce Compound (XIIa).

As the cyanating agent, for example, sodium cyanide, potassium cyanideand the like can be mentioned.

This reaction is generally carried out in a solvent that does notadversely affect the reaction.

As the solvent that does not adversely affect the reaction, for example,aromatic hydrocarbons such as benzene, toluene, xylene and the like;ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether,tetrahydrofuran, dioxane, dimethoxyethane and the like; esters such asmethyl acetate, ethyl acetate, n-butyl acetate, tert-butyl acetate andthe like; amides such as dimethylformamide, dimethylacetamide and thelike; sulfoxides such as dimethyl sulfoxide and the like; water and thelike can be mentioned. These solvents may be used in a mixture of two ormore kinds in appropriate ratios.

The amount of the cyanating agent to be used is generally 1 to 10 moleequivalents relative to Compound (Va).

The reaction temperature is generally −20 to 100° C.

The reaction time is generally 0.5-24 hrs.

This reaction may be carried out in the presence of a phase transfercatalyst (e.g., benzyl tributyl ammonium chloride, crown ethers(18-crown-6-ether, 15-crown-5-ether etc.). The amount of the phasetransfer catalyst to be used is, for example, 0.5 to 10 mole equivalentsrelative to Compound (Va).

Compound (XIIa) thus obtained may be isolated and purified by knownmeans of separation and purification such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, redissolution, chromatography andthe like. Alternatively, Compound (XIIa) may be used as a reactionmixture containing Compound (XIIa) for the next reaction withoutisolation.

[Method J]

Compound (I-6) can be also produced by, for example, subjecting acompound represented by the formula

wherein each symbol is as defined above, or a salt thereof to anoxidation reaction.

The oxidation reaction is carried out according to a conventional methodin the presence of an oxidizing agent in a solvent that does notadversely affect the reaction.

As the oxidizing agent, for example, manganese derivatives (e.g.,manganese dioxide, potassium permanganate 0.5 etc.), chromic acidderivatives (e.g., chromium(VI) oxide, dichromate, chromate, chromylchloride, chromic acid ester etc.), nitric acid, nickel peroxide and thelike can be used. As the oxidizing agent, a mixture of sodiumhypochlorite, sodium chlorite and the like, may be used with2,2,6,6-tetramethyl-1-piperidinyloxy radical as a catalyst foroxidation.

The amount of the oxidizing agent to be used is, for example, 1 to 10mole equivalents relative to Compound (XIII).

As the solvent that does not adversely affect the reaction, for example,halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; aliphatic hydrocarbons such as hexane,heptane and the like; ethers such as diethyl ether, diisopropyl ether,tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane andthe like; nitriles such as acetonitrile, propionitrile and the like;esters such as methyl acetate, ethyl acetate, n-butyl acetate,tert-butyl acetate and the like; amides such as dimethylformamide,dimethylacetamide and the like, and the like can be mentioned. Thesesolvents may be used in a mixture of two or more kinds in appropriateratios, and may be mixed with water and a buffer solution (e.g.,phosphate buffer etc.) before use.

The reaction temperature is generally −10 to 100° C., preferably 0 to40° C.

The reaction time is generally 0.1-20 hrs, preferably 0.1-10 hrs.

This reaction may be carried out in the presence of an acid or a base.

As the acid, for example, mineral acids (e.g., hydrochloric acid,hydrobromic acid, sulfuric acid etc.), carboxylic acids (e.g., formicacid, acetic acid, propionic acid etc.) and the like can be mentioned.

As the base, for example, alkali metal salts such as sodium hydroxide,potassium hydroxide, potassium carbonate, sodium carbonate, potassiumhydrogencarbonate, sodium hydrogencarbonate and the like; alkali metalalkoxides such as potassium methoxide, potassium ethoxide, sodiummethoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide andthe like; amines such as trimethylamine, triethylamine,ethyldiisopropylamine, N-methylmorpholine and the like; aromatic aminessuch as pyridine, lutidine, picoline and the like; and the like can bementioned. In some cases, these acids and bases may be used as asolvent.

The amount of the acid or base to be used is, for example, 1 to 200 moleequivalent relative to Compound (XIII).

Compound (I-6) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.

Of Compound (XIII) used as the starting compound in the above-mentionedMethod J, Compound (XIIIa) wherein U is a bond and W is —CH₂— can beproduced by, for example, subjecting a compound represented by theformula

wherein each symbol is as defined above, or a salt thereof, to areduction reaction.

The reduction reaction is carried out according to a conventional methodin the presence of a reducing agent in a solvent that does not adverselyaffect the reaction.

As the reducing agent, for example, reducing agent of metal hydridecompounds such as sodium bis(2-methoxyethoxy)aluminum hydride,duisobutylaluminum hydride and the like; metal hydride complex compoundssuch as sodium borohydride, sodium cyanoborohydride, lithium aluminumhydride and the like; and the like can be mentioned. Of these,diisobutylaluminum hydride is preferable.

The amount of the reducing agent to be used is, for example, about0.1—about 20 mole equivalents, relative to Compound (XIV).

As the solvent that does not adversely affect the reaction, for example,alcohols such as methanol, ethanol, propanol, 2-propanol, butanol,isobutanol, tert-butanol and the like; aromatic hydrocarbons such asbenzene, toluene, xylene and the like; aliphatic hydrocarbons, such ashexane, heptane and the like; ethers such as diethyl ether, diisopropylether, tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethaneand the like; nitriles such as acetonitrile propionitrile and the like;esters such as methyl acetate, ethyl acetate, n-butylbacetate,tert-butyl acetate and the like; amides such as dimethylformamide,dimethylacetamide and the like can be used. These solvents may be usedin a mixture of two or more kinds in appropriate ratios, and may bemixed with water and a buffet solution (e.g., phosphate buffer etc.)before use. Of these solvents, tetrahydrofuran, dimethoxyethane and thelike are preferable.

The reaction temperature is generally −70 to 150° C., preferably−20-100° C.

The reaction time is generally 0.1-100 hrs, preferably 0.1-40 hrs.

The reduction reaction can be also carried out in the presence of ametal catalyst such as palladium-carbon, palladium black, palladiumchloride, platinum oxide, platinum black, platinum-palladium,Raney-nickel, Raney-cobalt and the like, and a proton source, in asolvent that does not adversely affect the reaction.

The amount of the metal catalyst to be used is, for example, 0.01-1000mole equivalents, preferably 0.05-100 mole equivalents relative toCompound (XIV).

As the proton source, hydrogen gas, formic acid, amine formate,phosphinate, hydrazine and the like can be Mentioned.

As the solvent that does not adversely affect the reaction, those usedfor the aforementioned reduction reaction using the reducing agent canbe mentioned.

The reaction temperature and reaction time are the same as those in theaforementioned reduction reaction using a reducing agent.

Compound (XIIIa) thus obtained may be isolated and purified by knownmeans of separation and purification such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, redissolution, chromatography andthe like. Alternatively, Compound (XIIIa) may be used as a reactionmixture containing Compound (XIIIa) for the next reaction withoutisolation.

The above-mentioned Compound (XIV) can be produced by subjectingCompound (VI) to an epoxidation reaction.

The epoxidation reaction is carried out using, for example, a compoundrepresented by the formula: R¹⁷R¹⁸CH₃SO_(m)Lb (XV) wherein R¹⁷ and R¹⁸are the same or different and each is alkyl group, Lb is a halogen atomand m is 0 or 1, and a base.

As the alkyl group represented by R¹⁷ or R¹⁸, for example, alkyl grouphaving 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, pentyl, hexyl and the like can be mentioned. Of these,methyl is preferable.

As the halogen atom represented by Lb, for example, chlorine, bromine,fluorine, iodine and the like can be mentioned. Of these, bromine andiodine are preferable.

The amount of Compound (XV) to be used is, for example, 1-100 moleequivalents, preferably 1-10 mole equivalents relative to Compound (VI).

As the base, for example, alkali metal hydrides such as potassiumhydride, sodium hydride and the like; alkali metal salts such as sodiumhydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,potassium hydrogencarbonate, sodium hydrogencarbonate and the like;alkali metal alkoxides such as potassium methoxide, potassium ethoxide,sodium methoxide, sodium ethoxide, potassium t-butoxide, sodiumt-butoxide and the like; amines such as trimethylamine, triethylamine,ethyldiisopropylamine, N-methylmorpholine and the like; amides such aslithium diethylamide, lithium diisopropylamide and the like; and thelike can be mentioned. Of these, potassium t-butoxide, sodiumt-butoxide, sodium hydroxide, potassium hydroxide and the like arepreferable.

The amount of the base to be used is, for example, 1-100 moleequivalents, preferably 1-10 mole equivalents, relative to Compound(VI).

This reaction is generally carried out in a solvent that does notadversely affect the reaction. As such solvent, for example, alcoholssuch as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol,tert-butanol and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; aliphatic hydrocarbons such as hexane,heptane and the like; ethers such as diethyl ether, diisopropyl ether,tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane andthe like; nitriles such as acetonitrile, propionitrile and the like;esters such as methyl acetate, ethyl acetate, n-butyl acetate,tert-butyl acetate and the like; amides such as dimethylformamide,dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxideand the like; and the like can be mentioned. These solvents may be usedin a mixture of two or more kinds in appropriate ratios, and may bemixed with water and a buffer solution (e.g., phosphate buffer etc.)before use. Of these solvents, acetonitrile, tetrahydrofuran, dimethylsulfoxide and the like are preferable.

The reaction temperature is generally −50 to 150° C., preferably −20° C.to 100° C.

The reaction time is generally 0.1-20 hrs, preferably 0.1-10 hrs.

Compound (XIV) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.Alternatively, Compound (XIV) may be used as a reaction mixturecontaining Compound (XIV) for the next reaction without isolation.

Compound (XV) used as the starting compound in the above-mentionedreaction is obtained as, for example, a commercially available product.

Compound (VI) may be once converted to hydrogensulfite and thensubjected to an epoxidation reaction, wherein the use of hydrogensulfiteof Compound (VI) for the epoxidation reaction results in the productionof Compound (XIV) in a higher yield.

The hydrogensulfite of Compound (VI) can be produced by, for example,reacting Compound (VI) with an alkali metal hydrogensulfite. As thealkali metal hydrogensulfite, for example, sodium hydrogensulfite andthe like can be mentioned.

The amount of the alkali metal hydrogensulfite to be used is, generally1-20 mole equivalents, preferably 1-10 mole equivalents, relative toCompound (VI).

This reaction is generally carried out in a solvent that does notadversely affect the reaction. As such solvent, for example, alcoholssuch as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol,tert-butanol and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; aliphatic hydrocarbons such as hexane,heptane and the like; ethers such as diethyl ether, diisopropyl ether;tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane andthe like; nitrites such as acetonitrile, propionitrile and the like;esters such as methyl acetate, ethyl acetate, n-butyl acetate,tert-butyl acetate and the like; and the like can be mentioned. Thesesolvents may be used in a mixture of two or more kinds in appropriateratios, and may be mixed with water and a buffer solution (e.g.,phosphate buffer etc.) before use. Of these solvents tetrahydrofuran,isopropyl ether, ethyl acetate and the like are preferable.

The reaction temperature is generally −10 to 100° C., preferably 0 to50° C.

The reaction time is generally 0.1-30 hrs, preferably 0.5-20 hrs.

The hydrogensulfite of Compound (VI) thus obtained may be isolated andpurified by known means of separation and purification such asconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, redissolution, chromatography andthe like. Alternatively, hydrogensulfite of Compound (VI) may be used asa reaction mixture containing the hydrogensulfite for the next reactionwithout isolation.

When the hydrogensulfite of Compound (VI) can be used, this may beconverted to Compound (VI) and then subjected to an epoxidationreaction.

The reaction for obtaining Compound (VI) can be generally carried out inthe presence of an acid or a base.

Here, as the acid, for example, mineral acids (e.g., hydrochloric acid,hydrobromic acid, sulfuric acid etc.), carboxylic acids (e.g., formicacid, acetic acid, propionic acid etc.) and the like can be mentioned.Of these, acetic acid, formic acid and the like are preferable.

As the base, for example, alkali metal salts such as potassiumhydroxide, sodium hydroxide, potassium carbonate, sodium carbonate,potassium hydrogencarbonate, sodium hydrogencarbonate and the like;amines such as trimethylamine, triethylamine, ethyldiisopropylamine,N-methylmorpholine and the like; and the like can be mentioned. Ofthese, sodium carbonate, sodium hydroxide and the like are preferable.

The amount of the acid or base to be used is for example, 1-100 moleequivalents, preferably 1-50 mole equivalents, relative tohydrogensulfite of Compound (VI).

The reaction is generally carried out in a solvent that does notadversely affect the reaction. As such solvent, for example, alcoholssuch as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol,tert-butanol and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; aliphatic hydrocarbons such as hexane,heptane and the like; ethers such as diethyl ether, diisopropyl ether,tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane andthe like; nitrites such as acetonitrile, propionitrile and the like;esters such as methyl acetate, ethyl acetate, n-butyl acetate,tert-butyl acetate and the like; amides such as dimethylformamide,dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxideand the like; and the like can be mentioned. These solvents may be usedin a mixture of two or more kinds in appropriate ratios, and may bemixed with water and a buffer solution (e.g., phosphate buffer etc.)before use. Of these solvents, tetrahydrofuran, isopropyl ether, ethylacetate and the like are preferable.

The reaction temperature is generally 0 to 100° C., preferably 10 to 50°C.

The reaction time is generally 0.1-100 hrs, preferably 0.1-10 hrs.

Compound (VI) can be produced by, for example, subjecting a compoundrepresented by the formula:

wherein each symbol is as defined above, or a salt thereof, to areduction reaction.

The reduction reaction is carried out according to a conventional methodin the presence of a reducing agent in a solvent that does not adverselyaffect the reaction.

As the reducing agent, for example, the reducing agents of metal hydridecompounds such as sodium bis(2-methoxyethoxy)aluminum hydride, sodiumtriethoxyaluminum hydride, diisobutylaluminum hydride, triethoxy lithiumaluminum hydride, lithium tri-(tert-butoxy)aluminum hydride and thelike, and the like can be mentioned. Of these, diisobutylaluminumhydride is preferable.

The amount of the reducing agent to be used is, for example, 0.1-100equivalents, preferably 1-5 equivalents, relative to Compound (XVI).

As the solvent that does not adversely affect the reaction, for example,halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform and the like; aromatic hydrocarbons such as benzene, toluene,xylene and the like; aliphatic hydrocarbons such as hexane, heptane andthe like; ethers such as diethyl ether, diisopropyl ether,tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane andthe like; and the like can be mentioned. Of these, aromatic hydrocarbonssuch as toluene, xylene and the like are preferable.

The reaction temperature is generally −100° C. to 50° C., preferably−90° C. to 30° C.

The reaction time is generally 0.1-10 hrs, preferably 0.1-5 hrs.

The reduction reaction can be also carried out in the presence of ametal catalyst such as palladium-carbon, palladium black, palladiumchloride, platinum oxide, platinum black, platinum-palladium,Raney-nickel, Raney-cobalt and the like, and a proton source, in asolvent that does not adversely affect the reaction.

The amount of the metal catalyst to be used is for example 0.01-1000mole equivalents, preferably 0.05-100 mole equivalents, more preferably0.1-10 mole equivalents, relative to Compound (XVI).

As the proton source, hydrogen gas, mineral acids (e.g., hydrochloricacid, hydrobromic acid, sulfuric acid etc.), carboxylic acids (e.g.,formic acid, acetic acid, propionic acid etc.), phosphinate (e.g.,sodium phosphinate, potassium phosphinate etc.), amine formate,hydrazine and the like can be mentioned. Two or more kinds of theseproton sources may be used in combination. As the proton source, acombination of mineral acids (e.g., hydrochloric acid, hydrobromic acid,sulfuric acid etc.) or carboxylic acids (e.g., formic acid, acetic acid,propionic acid etc.) and phosphinate (e.g., sodium phosphinate,potassium phosphinate etc.) is particularly preferable.

The amount of the acid and phosphinate to be used is, generally 0.1-100mole equivalents, preferably 1-50 mole equivalents, relative to Compound(XVI), respectively.

The reduction reaction is preferably carried out using a metal catalystselected from Raney-nickel and Raney-cobalt, and a proton source whichis a combination of mineral acids (e.g., hydrochloric acid, hydrobromicacid, sulfuric acid etc.) or carbbxylic acids (e.g., formic acid, aceticacid, propionic acid etc.) and phosphinate (e.g., sodium phosphinate,potassium phosphinate etc.).

As the solvent that does not adversely affect the reaction, for example,alcohols such as methanol, ethanol, prbpanol, 2-propanol, butanol,isobutanol, tert-butanol and the like; aromatic hydrocarbons such asbenzene, toluene, xylene and the like; aliphatic hydrocarbons such ashexane, heptane and the like; ethers such as diethyl ether, diisopropylether, tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethaneand the like; aromatic amines such as pyridine, picoline, lutidine,quinoline and the like; and the like can be mentioned. These solventsmay be used in a mixture of two or more kinds in appropriate ratios, andmay be mixed with water and a buffer solution (e.g., phosphate bufferetc.) before use. Of these, pyridine is preferable.

When mineral acids, carboxylic acids and the like are used as a protonsource, these may be used as a solvent.

The reaction temperature is generally 0 to 100° C., preferably 20 to 80°C.

The reaction time is generally 0.1-100 hrs, preferably 0.5-10 hrs.

Compound (XVI) can be produced by, for example, the following method.

wherein each symbol is as defined above.

This reaction is, for example, carried out in the presence of a base ina solvent that does not adversely affect the reaction.

As the base, for example, alkali metal hydride such as potassiumhydride, sodium hydride and the like; alkali metal salt such aspotassium hydroxide, sodium hydroxide, potassium carbonate, sodiumcarbonate, potassium hydrogencarbonate, sodium hydrogencarbonate and thelike; alkali metal alkoxide such as potassium methoxide, sodiummethoxide, potassium ethoxide, sodium ethoxide, potassium-t-butoxide,sodium-t-butoxide and the like; amines such as trimethylamine,triethylamine, ethyldiisopropylamine, N-methylmorpholine and the like;and the like can be mentioned. Of these, sodium hydride, sodiumhydroxide, sodium-t-butoxide and the like are preferable.

The amount of the base to be used is, for example, 1-100 moleequivalents, preferably 1-10 mole equivalents, relative to Compound(II).

As the solvent that does not adversely affect the reaction, for examplealcohols such as methanol, ethanol, propanol, 2-propanol, butanol,isobutanol, tert-butanol and the like; aromatic hydrocarbons such asbenzene, toluene, xylene and the like; aliphatic hydrocarbons such ashexane, heptane and the like; ethers such as diethyl ether, diisopropylether, tert-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethaneand the like; nitrites such as acetonitrile, propionitrile and the like;esters such as methyl acetate, ethyl acetate, n-butyl acetate,tert-butyl acetate and the like; amides such as N,N-dimethylformamidedimethylacetamide and the like; sulfoxides such as dimethyl sulfoxideand the like; and the like can be mentioned. These solvents may be usedin a mixture of two or more kinds in appropriate ratios, and may bemixed with water and a buffer solution (e.g., phosphate buffer etc.)before use. Of these solvents, dimethylformamide and the like arepreferable.

The amount of Compound (XVII) to be used is, for example, 0.1-10 moleequivalents, preferably 0.3-3 mole equivalents, relative to Compound(II).

The reaction temperature is generally 0 to 100° C., preferably 10 to 50°C.

The reaction time is generally 0.1-100 hrs.

Compound (XVI) thus obtained may be isolated and purified by known meansof separation and purification such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, redissolution, chromatography and the like.Alternatively, Compound (XVI) may be used as a reaction mixturecontaining Compound (XVI) for the next reaction without isolation.

Compound (XVII) can be produced according to a method known per se.

When the starting compound has amino group, carboxy group, hydroxy groupor carbonyl group as a substituent in each reaction described above,these groups may have a protecting group in common use in peptidechemistry and other fields. The desired compound can be obtained byremoving the protecting group after the reaction, if necessary.

As the amino-protecting group, those exemplified for the aforementionedR⁶ can be mentioned.

Examples of the carboxy-protecting groups include C₁₋₆ alkyls (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C₇₋₁₁aralkyls (e.g., benzyl, etc.), phenyl, trityl, silyls (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C₂₋₆ alkenyls(e.g., 1-allyl, etc.), and the like. These groups may be substituted by1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.),C₁₋₆ alkoxys (e.g., methoxy, ethoxy, propoxy, etc.), nitro, or the like.

As the hydroxy-protecting group, those exemplified for theaforementioned R⁵ can be mentioned.

Examples of the carbonyl-protecting groups include cyclic acetals (e.g.,1,3-dioxane, etc.), acyclic acetals (e.g., di-C₁₋₆ alkylacetals, etc.),and the like.

In addition, these protecting groups can be removed according to amethod known per se, e.g., the method described in Protective Groups inOrganic Synthesis, published by John Wiley and Sons (1980) and the like.For example, there may be used methods employing an acid, a base,ultraviolet rays, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride palladium acetate,a trialkylsilylkhalide (e.g., trimethylsilyl iodide, trimethylsilylbromide, etc.), or the like, the reduction method, and the like.

When Compound (I) contains an optical isomer, a stereoisomer, aregioisomer, or a rotational isomer, these isomers are also contained asCompound (I) and can each be obtained as a single substance by means ofa method known per se of synthesis or separation. For example, when anoptical isomers are present in Compound (I), the optical isomersseparated from said compound are also included in Compound (I).

Optical isomers can be produced by a method known per se. Specifically,optical isomers are obtained by using an optically active syntheticintermediate, or optically resolving a racemate of the final product bya conventional method.

Examples of the methods of optical resolution include methods known perse, such as the fractional recrystallization method, the chiral columnmethod, the diastereomer method, and the like.

1) Fractional Recrystallization Method

A method wherein salts are formed between a racemate and an opticallyactive compound [e.g., (+)-mandelic acid, (−)-mandelic acid,(+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine,(−)-1-phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.],which salts are separated by fractional recrystallization and, ifdesired, subjected to a neutralization process, to yield free opticalisomers.

2) Chiral Column Method

A separating method wherein a racemate or a salt thereof is applied to aseparation column for optical isomer (chiral column). In the case ofliquid chromatography, for example, optical isomers are separated byadding a mixture of the optical isomers to a chiral column such asENANTIO-OVM (produced by Tosoh Corporation) or CHIRAL series produced byDAICEL CHEMICAL IND., and the like and developing it in water, variousbuffers (e.g., phosphate buffer), an organic solvent (e.g., ethanol,methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine,etc.), or a solvent mixture thereof. In the case of gas chromatography,for example, a chiral column such as CP-Chirasil-DeX CB (produced by GLScience) and the like is used to separate optical isomers.

3) Diastereomer Method

A method wherein a racemate mixture and an optically active reagent arechemically reacted to yield a diastereomer mixture, which is thensubjected to ordinary means of separation (e.g., fractionalrecrystallization, chromatography method, etc.) and the like to obtainsingle substances, which are subjected to a chemical treatment such ashydrolysis to cut off the optically active reagent moiety, whereby thedesired optical isomer is obtained. For example, when Compound (I) hashydroxy or primary or secondary amino in the molecule thereof, saidcompound, an optically active organic acid (e.g., MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (−)-menthoxyaceticacid, etc.) and the like may be subjected to a condensing reaction toyield a diastereomer of an ester or amide, respectively. On the otherhand, when Compound (I) has a carboxyl group, said compound and anoptically active amine or alcohol reagent may be subjected to acondensing reaction to yield a diastereomer of an amide or ester,respectively. The diastereomer thus separated is converted to an opticalisomer of the original compound by subjecting it to an acid hydrolysisor basic hydrolysis reaction.

The present invention is hereinafter described in more detail by meansof, but is not limited to, the following Test Examples, ReferenceExamples, Examples and Preparation Examples.

In addition, % in the Reference Examples and Examples below meanspercent by weight, unless mentioned otherwise. Room temperature meansthe temperature of 1 to 30° C.

Abbreviations for bases, amino acids and others used in the presentspecification are based on abbreviations specified by the IUPAC-IUBCommission on Biochemical Nomenclature or abbreviations in common use inrelevant fields. Some examples are given below. When an optical isomermay be present in amino acid, it is of the L-configuration, unlessotherwise mentioned.

The sequence numbers in the sequence listing in the presentspecification show the following respective sequences.

-   [SEQ ID NO:1]-   Shows the base sequence of the primer PAG-U used in Reference    Example 1.-   [SEQ ID NO:2]-   Shows the base sequence of the primer PAG-L used in Reference    Example 1.-   [SEQ ID NO:3]-   Shows the base sequence of the primer XRA-U used in Reference    Example 2.-   [SEQ ID NO:4]-   Shows the base sequence of the primer XRA-L used in Reference    Example 2.-   [SEQ ID NO:5]-   Shows the base sequence of PPRE-U used in Reference Example 4.-   [SEQ ID NO:6]-   Shows the base sequence of PPRE-L used in Reference Example 4.-   [SEQ ID NO:7]-   Shows the base sequence of the primer TK-U used in Reference Example    4.-   [SEQ ID NO:8]-   Shows the base sequence of the primer TK-L used in Reference Example    4.

EXAMPLES Test Example 1

Hypoglycemic and Hypolipidemic Actions in Mice

Test compounds were mixed in a powdery diet (CE-2, Japan Clea) at theconcentration of 0.01% (compounds of Examples 7, 26, 29, 32) or 0.005%(compounds of Examples 1, 11, 15, 18, 24, 36, 37, 41, 48, 50, 51, 52,58, 62, 79, 83, 88, 90, 91, 92, 93, 97, 107, 110, 115, 119, 122, 125,129 and 130), and freely given to KKAY mice (11 to 12 weeks old, 5 micein a group), a model of type 2 diabetes mellitus, for four days. Duringthis period, water was given freely. Blood was sampled from orbitalvenous plexus, and glucose and triglyceride levels in plasma separatedfrom blood were determined enzymatically using L type Wako Glu2 (WakoPure Chemical Industries, Ltd.) or L type Wako TG.H (Wako Pure ChemicalIndustries, Ltd.), respectively. The results are given in Table 1.

In the Table, “hypoglycemic action (%)” means a percent reduction (%) ofthe glucose level in the test compound administration group when that ofthe test compound non-administration group is taken as 100%. Inaddition, the “hypolipidemic action (%)” means a percent reduction (%)of the triglyceride level in the test compound administration group whenthat of the test compound non-administration group is taken as 100%.

TABLE 1 test compound hypoglycemic action hypolipidemic action (Examplenumber) (%) (%) 1 21 33 7 48 62 11 56 84 15 49 60 18 41 34 24 49 67 2653 88 29 58 67 32 40 53 36 55 71 37 50 61 41 48 93 48 53 50 50 54 77 5155 79 52 56 61 58 57 75 62 47 44 79 54 96 83 48 43 88 47 90 90 30 40 9150 67 92 58 83 93 45 53 97 34 83 107 40 39 110 51 74 115 52 87 119 40 33122 52 67 125 41 40 129 45 93 130 55 63

These results indicated that the compounds of the present inventionpossess potent hypoglycemic and hypolipidemic actions. Therefore, thepresent compounds are useful as prophylactic or therapeutic agents ofdiabetes mellitus, hyperlipidemia (especially hypertriglyceridemia),impaired glucose tolerance, etc.

Test Example 2

Total Cholesterol Lowering Action and Plasma Anti-arteriosclerosis IndexEnhancing Action in Mice

Test compounds were mixed in a powdery diet (CE-2, Japan Clea) theconcentration of 0.01% (compounds of Examples 7, 26, 29 and 32) or0.005% (compounds of Examples 1, 11, 15, 18, 24, 36, 37, 41, 48, 50, 51,52, 58, 62, 79, 88, 91, 92, 93, 97, 107, 110, 129 and 130), and freelygiven to KKA^(y) mice (11 to 12 weeks old, 5 mice per group), a model oftype-2 diabetes mellitus, for four days. During this period, water wasgiven freely. Blood was sampled from orbital venous plexus andcomponents were analyzed using the plasma separated from the blood.Total cholesterol levels were determined by using L type WakoCholesterol (Wako Pure Chemical Industries, Ltd). Precipitation reagentfor HDL cholesterol (Wako Pure Chemical Industries, Ltd.) was added to apart of the plasma to precipitate non-HDL lipoprotein, and cholesterol(HDL cholesterol) in the resulting supernatant was determined. Theplasma anti-arteriosclerosis index [(HDL cholesterol/totalcholesterol)×100] was calculated by using these cholesterol levels. Theresults are given in Table 2.

In the Table, “Total cholesterol lowering action (%)” represents thepercent reduction (%) of total cholesterol level in the test compoundadministration group, when the total cholesterol level in the testcompound non-administration group is taken as 100%. “Plasmaanti-arteriosclerosis index-enhancing action (%)” represents the percentincrease (%) of plasma anti-arteriosclerosis index in the test compoundadministration group, when the plasma anti-arteriosclerosis index in thetest compound non-administration group is taken as 100%.

TABLE 2 plasma total cholesterol anti-arteriosclerosis test compoundlowering action index-enhancing action (Example number) (%) (%) 1 7 11 717 15 11 23 18 15 25 4 18 23 12 24 10 17 26 20 16 29 21 20 32 2 10 36 1934 37 15 19 41 25 28 48 17 20 50 20 15 51 24 22 52 26 15 58 20 21 62 915 79 39 42 88 10 22 91 6 16 92 15 23 93 16 17 97 27 27 107 13 9 110 2124 129 14 25 130 16 15

These results indicated that the compounds of the present inventionpossess total cholesterol lowering and plasma anti-arteriosclerosisindex-enhancing actions. Therefore, the present compounds are proved tobe useful as prophylactic or therapeutic agents of arteriosclerosis andthe like, by improving plasma lipoprotein profiles ofhypercholesterolemia or hypo-HDL-cholesterolemia.

Test Example 3

(PPARγ-RXRα Heterodimer Ligand Activity)

A PPARγ:RXRα:4ERPP/CHO-K1 cells obtained in Reference Example 5described later were cultured in HAM F12 medium (produced by NISSUISEIYAKU) containing 10% Fetal bovine serum (produced by LifeTechnologies, Inc., USA) and then inoculated to a 96-well white plate(produced by Corning Costar Corporation, USA) at the density of 2×10⁴cells/well, and cultured in a CO₂ gas incubator at 37° C. overnight.

After washing the 96 well white plate with PBS (Phosphate-bufferedsaline), 90 μl of HAM F12 medium containing 0.1% fatty acid-free bovineserum albumin (BSA) and 10 μl of test compound were added, which wascultured in a CO₂ gas incubator at 37° C. for 48 hours. After removingthe medium, 40 μl of PIKKAGENE 7.5 (produced by Wako Pure ChemicalIndustries, Ltd.) was added. After stirring, the luciferase activity wasdetermined using Lumistar (produced by BMG Labtechnologies GmbH,Germany).

A fold induction was calculated based on the luciferase activity of eachtest compound by taking the luciferase activity in the test compound nonadministration group as 1. The values of the test compound,concentration and the fold induction were analyzed using PRISM 2.01(produced by GraphPad Software Inc. USA) to calculate the EC₅₀ values,the effective concentration of a test compound for 50% of the maximumfold induction. The results are shown in Table 3.

TABLE 3 test compound EC₅₀ (Example number) (μM) 1 0.29 7 0.036 11 0.06215 0.20 18 2.90 24 0.16 26 0.035 29 0.025 32 0.077 36 0.033 37 0.61 410.015 48 0.018 50 0.18 51 1.20 52 0.23 58 0.12 60 0.0061 62 0.020 660.94 71 0.33 78 0.19 79 0.0092 81 0.062 83 0.11 85 0.26 88 0.0071 900.052 91 0.0017 92 0.37 93 0.39 97 0.026 99 0.16 101 0.043 103 0.24 1070.087 110 0.042 115 0.070 119 0.22 122 0.017 124 0.042 125 0.13 126 1.70129 0.059 130 0.011 132 0.11

These results indicated that the compounds of the present invention havepotent PPARγ-RXRα heterodimer ligand activity.

Reference Example 1

(Human PPARγ Gene Cloning)

A human PPARγ gene was cloned using a heart cDNA (produced by ToyoboCo., Ltd., trade name: QUICK-Clone cDNA) as a template by means of a PCRmethod employing a primer set shown below which was prepared withreference to the base sequence of PPARγ gene reported by Greene et al(Gene Expr., 1995, Vol. 4(4-5), page 281-299).

-   PAG-U: 5′-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA GAG-3′ (Sequence    ID Number: 1)-   PAG-L: 5′-GGG GTC GAC CAG GAC TCT CTG CTA GTA CAA GTC-3′ (Sequence    ID Number: 2)

The PCR reaction was performed by Hot Start method using AmpliWax PCRGem 100 (produced by TAKARA SHUZO CO., LTD.). First, 2 μl of 10×LA PCRBuffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl each of 12.5 μM primersolutions and 10 μl of sterilized distilled water were mixed to obtain abottom layer solution mixture. 1 μl of human heart cDNA (1 ng/ml) as atemplate, 3 μl of 10×LA PCR Buffer, 1 μl of 2.5 mM dNTP solution, 0.5 μlof TaKaRa LA Taq DNA polymerase (produced by TAKARA SHUZO CO., LTD.) and24.5 μl of sterilized distilled water were mixed to obtain a top layersolution mixture.

To the bottom layer solution, mixture described above, added was oneunit of AmpliWax PCR Gem 100 (produced by TAKARA SHUZO CO., LTD.), whichwas treated at 70° C. for 5 minutes and then in ice for 5 minutes. Thenthe top layer solution mixture was added to the mixture to prepare thereaction mixture of PCR. A tube containing the reaction mixture was seton a thermal cycler (produced by Perkin Elmer, USA) and treated at 95°C. for 2 minutes. After repeating the cycle of 95° C. for 15 seconds and68° C. for 2 minutes a further 35 times, the tube was treated at 72° C.for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 1.4 kb DNA fragment containing PPARγ gene wasrecovered from the gel, and then inserted into pT7 Blue-T vector(produced by TAKARA SHUZO CO., LTD.) to obtain a plasmid pTBT-hPPARγ.

Reference Example 2

(Human RXRα Gene Cloning)

A human RXRα gene was cloned using a kidney cDNA (produced by ToyoboCo., Ltd., trade name: QUICK-Clone cDNA) as a template by means of a PCRmethod employing a primer set shown below which was prepared withreference to the base sequence of RXRα gene reported by Mangelsdorf, D.J. et al (Nature, 1990, Vol. 345 (6272), page 224-229).

XRA-U: 5′-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC CTG-3′ (Sequence IDNumber: 3) XRA-L: 5′-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3′(Sequence ID Number: 4)

The PCR reaction was performed by Hot Start method using AmpliWax PCRGem 100 (produced by TAKAEA SHUZO CO., LTD.). First, 2 μl of 10×LA PCRBuffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl each of 12.5 μM primersolutions and 10 μl of sterilized distilled water were mixed to obtain abottom layer solution mixture. 1 μl of human kidney cDNA (1 ng/ml) as atemplate, 3 μl of 10×LA PCR Buffer, 1 μl of 2.5 mM dNTP solution, 0.5 μlof TaKaRa LA Taq DNA polymerase (produced by TAKARA SHUZO CO., LTD.) and24.5 μl of sterilized distilled water were mixed to obtain a top layersolution mixture.

To the bottom layer solution mixture described above, added was one unitof AmpliWax PCR Gem 100 (produced by TAKARA SHUZO CO., LTD.), which wastreated at 70° C. for 5 minutes and then in ice for 5 minutes. Then, thetop layer solution mixture was added to the mixture to prepare thereaction mixture for PCR. A tube containing the reaction mixture was seton a thermal cycler (produced by Perkin Elmer, USA) and treated at 95°C. for 2 minutes. After repeating the cycle of 95° C. for 15 seconds and68° C. for 2 minutes a further 35 times, the tube was treated at 72° C.for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 1.4 kb DNA fragment containing RXRα gene wasrecovered from the gel, and then inserted into pT7 Blue-T vector(produced by TAKARA SHUZO CO., LTD.) to obtain a plasmid pTBT-hRXRα.

Reference Example 3

(Construction of Plasmids for Expressing Human PPARγ, RXRα)

A 7.8 kb. FspI-NotI fragment of plasmid pVgRXR (produced by Invitrogen,USA) was ligated to a 0.9 kb FspI-NotI fragment containing RXRα gene ofplasmid pTBT-hRXRα obtained in Reference Example 2 to prepare plasmidpVgRXR2. Then, pVgRXR2 was digested with BstXI and then treated withT4DNA polymerase (produced by TAKARA SHUZO CO., LTD.) to obtain a bluntterminal. Then digestion at KpnI gave a 6.5 kb DNA fragment.

On the other hand, plasmid pTBT-hPPARγ obtained in Reference Example 1was digested with Sal I and then treated with T4DNA polymerase (producedby TAKARA SHUZO CO., LTD.) to obtain a blunt terminal. Then digestion atKpnI gave a 1.4 kb DNA fragment containing human PPARγ gene.

The both DNA fragments were ligated to construct plasmid pVgRXR2-hPPARγ.

Reference Example 4

(Construction of Reporter Plasmids)

A DNA fragment containing PPAR-responding element (PPRE) of an acyl-CoAoxidase was prepared using the following 5′-terminal phosphorylatedsynthetic DNA.

PPRE-U: 5′-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-3′ (Sequence ID Number:5) PPRE-L: 5′-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-3′ (Sequence IDNumber: 6)

First, PPRE-U and PPRE-L were annealed and inserted to Sal I site ofplasmid pBlue Script SK+. By determining the base sequence of theinserted fragment, plasmid pBSS-PPRE4 in which 4 PPREs were ligated intandem was selected.

A HSV thymidine kinase minimum promoter (TK promoter) region was clonedusing pRL-TK vector (produced by Promega, USA) as a template by means ofa PCR method employing a primer set shown below which was prepared withreference to the base sequence of the promoter region of thymidinekinase gene reported by Luckow, B. et al (Nucleic Acids Res., 1987, Vol.15(13), p. 5490)

TK-U: 5′-CCCAGATCTCCCCAGCGTCTTGTCATTG-3′ (Sequence ID Number: 7) TK-L:5′-TCACCATGGTCAAGCTTTTAAGCGGGTC-3′ (Sequence ID Number: 8)

The PCR reaction was performed by Hot Start method using AmpliWax PCRGem 100 (TAKARA SHUZO CO., LTD.). First, 2 μl of 10×LA PCR Buffer, 3 μlof 2.5 μM dNTP solution, 2.5 μl each of 12.5 μM primer solutions and 10μl of sterilized distilled water were mixed to obtain a bottom layersolution mixture. 1 μl of pRL-TK vector (produced by Promega, USA) as atemplate, 3 μl of 10×LA PCR Buffer, 1 μl of 2.5 mM dNTP solution, 0.5 μlof TaKaRa LA Taq DNA polymerase (produced by TAKARA SHUZO CO., LTD.) and24.5 μl of sterilized distilled water were mixed to obtain a top layersolution mixture.

To the bottom layer solution mixture described above, added was one unitof AmpliWax PCR Gem 100 (produced by TAKARA SHUZO CO., LTD.), which wastreated at 70° C. for 5 minutes and then in ice for 5 minutes. Then, thetop layer solution mixture was added to the mixture to prepare thereaction mixture for PCR. A tube containing the reaction mixture was seton a thermal cycler (produced by Perkin Elmer, USA) and treated at 95°C. for 2 minutes. After repeating the cycle of 95° C. for 15 seconds and68° C. for 2 minutes a further 35 times, the tube was treated at 72° C.for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 140 b DNA fragment containing TK promoter wasrecovered from the gel, and then inserted into pT7 Blue-T vector(produced by TAKARA SHUZO CO., LTD.). By digesting the plasmid thusobtained with the restriction enzymes Bgl II and NcoI, a fragmentcontaining TK promoter was obtained, which was ligated to the BglII-NcoI fragment of plasmid pGL3-Basic vector (produced by Promega, USA)to obtain plasmid pGL3-TK.

A 4.9 kb NheI-XhoI fragment of plasmid pGL3-TK thus obtained was ligatedto a 200 b NheI-XhoI fragment of plasmid pBSS-PPRE4 to obtain plasmidpGL3-4ERPP-TK.

This plasmid pGL3-4ERPP-TK thus obtained was digested with BamHI(produced by TAKARA SHUZO CO., LTD.) and then treated with T4DNApolymerase (produced by TAKARA SHUZO CO., LTD.) to form a bluntterminal, whereby obtaining a DNA fragment.

On the other hand, pGFP-C1 (produced by Toyobo Co., Ltd.) was digestedwith Bsu36I (NEB) and then treated with T4DNA polymerase (produced byTAKARA SHUZO CO., LTD.) to form a blunt terminal whereby obtaining a 1.6kb of a DNA fragment.

The both DNA fragments were ligated to construct a reporter plasmidpGL3-4ERPP-TK neo.

Reference Example 5

(Introduction of Human PPARγ and RXRα Expressing Plasmid and ReporterPlasmid into CHO-K1 Cell and Establishment of Expressed Cell)

After a CHO-K1 cell cultured in a 750 ml tissue culture flask (producedby Corning-Costar Corporation, USA) containing HAM F12 medium (producedby NISSUI SEIYAKU) supplemented with 10% Fetal Bovine Serum (produced byLife Technologies, Inc., USA) was scraped by treating with 0.5 g/Ltrypsin-0.2 g/L EDTA (ethylenediaminetetraacetic acid) (produced by LifeTechnologies, Inc., USA), the cell was washed with PBS (phosphatebuffered saline) (produced by Life Technologies, Inc., USA), centrifuged(1000 rpm, 5 minutes), and then suspended in PBS. Subsequently, a DNAwas introduced into the cell under the condition shown below using GENEPULSER (produced by Bio-Rad Laboratories, USA).

Namely, to a cuvette having a 0.4 cm gap, added were 8×10⁶ cells and 10μg of plasmid pVgRXR2-hPPARγ obtained in Reference Example 3 and 10 μgof reporter plasmid pGL3-4ERPP-TK neo obtained in Reference Example 4,which was subjected to electroporation at the voltage of 0.25 kV underthe capacitance of 960 μF. Subsequently, the cell was transferred into aHAM F12 medium containing 10% Fetal Bovine. Serum and cultured for 24hours. Then the cell was scraped again and centrifuged, and thensuspended in HAM F12 medium containing 10% Fetal Bovine Serumsupplemented with 500 μg/ml of GENETICIN (produced by Life Technologies,Inc., USA) and 250 μg/ml of ZEOCIN (produced by Invitrogen, USA). Thesuspension was diluted to the density of 10⁴ cells/ml, and inoculated toa 96-well plate (produced by Corning Costar Corporation, USA), which wascultured in a CO₂ gas incubator at 37° C., whereby obtaining aGENETICIN- and ZEOCIN-resistant transformant.

Subsequently, after the transformant cell line thus obtained wascultured in a 24-well plate (produced by Corning Costar Corporation,USA), selected was a cell line, PPARγ:RXRα:4ERPP/CHO-K1 cell, in whichthe luciferase was expressed and induced by addition of 10 μMpioglitazone hydrochloride.

Reference Example 6

A mixture of 2,5-dihydroxybenzaldehyde (9.81 g), ethyl iodide (13.29 g),anhydrous potassium carbonate (14.72 g) and N,N-dimethylformamide (100mL) was stirred at room temperature for 1 hr. The reaction mixture waspoured into water and extracted with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated. The obtained residue was subjected to silica gelcolumn a chromatography to give crystals (4.20 g, 36%) of2-ethoxy-5-hydroxybenzaldehyde from a fraction eluted with ethylacetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexanegave pale-yellow prism crystals. melting point: 108-109° C.

Reference Example 7

A mixture of 2-ethoxy-5-hydroxybenzaldehyde (3.72 g), benzyl bromide(5.75 g), anhydrous potassium carbonate (3.10 g) andN,N-dimethylformamide (50 mL) was stirred at 90° C. for 3 hrs. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (5.06 g, 88%) of5-benzyloxy-2-ethoxybenzaldehyde from a fraction eluted with ethylacetate-hexane (1:4, v/v). Redrystallization from ethyl, acetate-hexanegave colorless prism crystals. melting point: 81-82° C.

Reference Example 8

A mixture of methyl methylthiomethyl sulfoxide. (0.30 g) and finelytriturated sodium hydroxide (0.015 g) was stirred at 70° C. for 30 min.To the reaction mixture was added 5-benzyloxy-2-ethoxybenzaldehyde (0.30g), and the mixture was further stirred at 70° C. for 1.5 hrs. To thereaction mixture was added ethyl acetate, and the organic layer waswashed successively with 1N hydrochloric acid and saturated brine, driedover anhydrous magnesium sulfate, and concentrated. A mixture of theobtained residue and 10% hydrogen chloride-methanol (15 mL) was heatedunder reflux for 15 hrs. To the reaction mixture was added ethylacetate. The organic layer was washed successively with saturatedaqueous sodium hydrogencarbonate and saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The obtained residue wassubjected to silica gel column chromatography to give methyl2-(2-ethoxy-5-hydroxyphenyl)acetate as a colorless oil (0.11 g, 44%)from a fraction eluted with ethyl acetate-hexane (1:4, v/v).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.0 Hz), 3.59 (2H, s), 3.70 (3H, s),3.96 (2H, t, J=7.0 Hz), 4.81 (1H, s), 6.65-6.76 (3H, m).

Reference Example 9

To a mixture of triethyl phosphonoacetate (1.93 g),5-benzyloxy-2-ethoxybenzaldehyde (2.00 g) and N,N-di methylformamide (50mL) was added sodium hydride. (60%, oil, 0.38 g) under ice-cooling. Thereaction mixture was stirred at room temperature for 3 hrs. Water wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed successively with water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained crystals were washed with hexane to givecrystals (2.01 g, 79%) of ethyl(E)-3-(5-benzyloxy-2-ethoxyphenyl)-2-propenoate. Recrystallization fromethyl acetate-hexane gave colorless prism crystals. melting point:124-125° C.

Reference Example 10

A mixture of ethyl (E)-3-(5-benzyloxy-2-ethoxyphenyl)-2-propenoate (1.85g), 5% palladium carbon (3.0 g), ethanol (50 mL) and tetrahydrofuran (30mL) was subjected to catalytic hydrogenation at room temperature and 1atm. After filtering off the catalyst, the solvents were evaporatedunder reduced pressure. The obtained residue was subjected to silica gelcolumn chromatography to give ethyl3-(2-ethoxy-5-hydroxyphenyl)propionate as a colorless oil (1.30 g, 96%)from a fraction eluted with ethyl acetate-hexane (1:4, v/v).

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.0 Hz), 1.39 (3H, t, J=7.0 Hz),2.55-2.63 (2H, m), 2.85-2.93 (2H, m), 3.97 (2H, q, J=7.0 Hz), 4.13 (2H,q, J=7.0 Hz), 4.66 (1H, s), 6.59-6.72 (3H, m).

Reference Example 11

To a mixture of dimethyl sulfoxide (70 mL) and tetrahydrofuran (200 mL)was added sodium hydride (60%, oil, 1.29 g) at room temperature. Afterstirring at 50° C. for 1.5 hrs., the reaction mixture was cooled to roomtemperature. Thereto was added ethyl triphenyl phosphonium bromide (9.76g) and the mixture was stirred at room temperature for 30 min. To thismixture was dropwise added further a solution (10 mL) of2-benzyloxy-4-methoxymethoxybenzaldehyde (5.50 g) in dimethyl sulfoxide.The mixture was heated under reflux for 1 hr. Water was added to thereaction mixture, and the mixture was neutralized by adding 1Nhydrochloric acid (33 mL) and extracted with ethyl acetate. The organiclayer was washed successively with water and saturated brine dried overanhydrous magnesium sulfate, and concentrated. The obtained residue wassubjected to silica gel column chromatography to give an oil (4.94 g)from a fraction eluted with ethyl acetate-hexane (9, v/v). A mixture ofthis oil, 5% palladium carbon (10.0 g) and tetrahydrofuran (300 mL) wassubjected to catalytic hydrogenation at room temperature and 1 atm.After filtering off the catalyst, the solvent was evaporated underreduced pressure. The obtained residue was subjected to silica gelcolumn chromatography to give 2-hydroxy-4-methoxymethoxy-1-propylbenzeneas a colorless oil (3.3 g, 83%) from a fraction eluted with ethylacetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 0.96 (3H, t, J=7.2 Hz), 1.51-1.66 (2H, m), 2.51 (2H,t, J=7.6 Hz), 3.47 (3H, s), 4.76 (1H, s), 5.13 (2H, s), 6.50-6.59 (2H,m), 7.00 (1H, d, J=8.0 Hz).

Reference Example 12

To a mixture of 2-hydroxy-4-methoxymethoxy-1-propylbenzene (1.50 g),methyl bromoacetate (1.39 g) and N,N-dimethylformamide (20 mL) was addedsodium hydride (60%, oil, 1.50 g) under ice-cooling. The reactionmixture was stirred at room temperature for 13 hrs. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give methyl2-(5-methoxymethoxy-2-propylphenoxy)acetate as a colorless oil (1.60 g,78%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.2 Hz), 1.51-1.66 (2H, m), 2.58 (2H,t, J=7.6 Hz), 3.47 (3H, s), 3.80 (3H, s), 4.62 (2H, s), 5.12 (2H, s),6.43 (1H, d, J=2.4 Hz), 6.62 (1H, dd, J=8.4, 2.4 Hz), 7.04 (1H, d, J=8.4Hz).

Reference Example 13

A mixture of methyl 2-(5-methoxymethoxy-2-propylphenoxy)acetate (1.60 g)and 10% hydrogen chloride-methanol (50 mL) was stirred at roomtemperature for 3 hrs. The reaction mixture was concentrated, and ethylacetate was added to the residue. The mixture was washed successivelywith saturated aqueous sodium hydrogencarbonate and saturated brine,dried over anhydrous magnesium sulfate, and concentrated to give methyl2-(5-hydroxy-2-propylphenoxy)acetate as a colorless oil (1.17 g, 87%).

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.4 Hz), 1.49-1.68 (2H, m), 2.56 (2H,t, J=7.6 Hz), 3.80 (3H, s), 4.61 (2H, s), 5.02 (1H, brs), 6.25 (1H; d,J=2.6 Hz), 6.38 (1H, dd, J=8.2, 2.6 Hz), 6.97 (1H, d, J=8.2 Hz).

Reference Example 14

To a mixture of 2-benzyloxy-5-hydroxybenzaldehyde (16.68 g) andN,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 3.07g) under ice-cooling, and the mixture was stirred at room temperaturefor 30 min. Chloromethyl methyl ether (11.8 g) was dropwise added to thereaction mixture. The reaction mixture was further stirred at roomtemperature for 3 hrs. The reaction mixture was poured into water andextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give 2-benzyloxy-5-methoxymethoxybenzaldehyde as acolorless oil (10.32 g, 52%) from a fraction eluted with ethylacetate-hexane (1:4, v/v).

¹H-NMR (CDCl₃) δ: 3.47 (3H, s), 5.14 (2H, s), 5.16 (2H, s), 6.97-7.01(1H, m), 7.19-7.25 (1H, m), 7.34-7.43 (5H, m), 7.42-7.51 (1H, m), 10.50(1H, s).

Reference Example 15

To a mixture of 2-benzyloxy-5-methoxymethoxybenzaldehyde (10.03 g),ethanol (50 mL) and tetrahydrofuran (100 mL) was added sodiumtetrahydroborate (1.43 g) under ice-cooling, and the mixture was stirredat room temperature for 1 hr. To the reaction mixture was added waterand the mixture was extracted with ethyl acetate. The organic layer waswashed successively with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated to give(2-benzyloxy-5-methoxymethoxyphenyl)methanol as a colorless oil (10.08g, 97%).

¹H-NMR (CDCl₃) δ: 2.31 (1H, t, J=6.6 Hz), 3.49 (3H, s), 4.71 (2H, d,J=6.6 Hz), 5.09 (2H, s), 5.13 (2H, s), 6.85-6.98 (2H, m), 7.04-7.06 (1H,m), 7.33-7.43 (5H, m).

Reference Example 16

A mixture of (2-benzyloxy-5-methoxymethoxyphenyl)methanol (8.0 g),triphenylphosphine (7.66 g), carbon tetrabromide (9.68 g) andN,N-dimethylformamide (100 mL) was stirred at room temperature for 1.5hrs. To the reaction mixture was added water and the mixture wasextracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, dried over anhydrous magnesium sulfate,and concentrated. The obtained residue was subjected to silica gelcolumn chromatography to give crystals (4.49 g, 46%) of1-benzyloxy-2-bromomethyl-4-methoxymethoxybenzene from a fraction elutedwith ethyl acetate-hexane (1:4, v/v). Recrystallization from ethylacetate-hexane gave colorless prism crystals. melting point: 55-57° C.

Reference Example 17

To a mixture of 1-benzyloxy-2-bromomethyl-4-methoxymethoxybenzene (0.30g) and dimethyl sulfoxide (3 mL) was added an aqueous solution (0.3 mL)of sodium cyanide (0.05 g) at room temperature and the mixture wasstirred for 13 hrs. To the reaction mixture was added water and themixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated to give2-(2-benzyloxy-5-methoxymethoxyphenyl)acetonitrile as a colorless oil(0.23 g, 92%).

¹H-NMR (CDCl₃) δ: 3.48 (3H, s), 3.69 (2H, s), 5.07 (2H, s), 5.12 (2H,s), 6.86 (1H, d, J=9.0 Hz), 6.97 (1H, dd, J=9.0, 2.6 Hz), 7.09 (1H, d,J=2.6 Hz), 7.32-7.45 (5H, m).

Reference Example 18

A mixture of 2-(2-benzyloxy-5-methoxymethoxyphenyl)acetonitrile (2.95g), 5% palladium carbon (2.0 g) and tetrahydrofuran (100 mL) wassubjected to catalytic hydrogenation at room temperature and 4.8 atm.After filtering off the catalyst, the solvent was evaporated underreduced pressure to give crystals (1.88 g, 94%) of2-(2-hydroxy-5-methoxymethoxyphenyl)acetonitrile. Recrystallization fromethyl acetate-hexane gave pale-brown prism crystals. melting point:68-69° C.

Reference Example 19

To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.95 g), 2-(2-hydroxy-5-methoxymethoxyphenyl)acetonitrile (1.0 g) andN,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.23g) under ice-cooling, and the mixture was stirred at 80° C. for 1 hr.The reaction mixture was poured into water and extracted with ethylacetate. The organic, layer was washed successively with water, 2Naqueous sodium hydroxide solution and saturated brine, and dried overanhydrous magnesium sulfate. After concentration of the organic layer,the residue was subjected to silica gel column chromatography to givecrystals (1.40 g, 57%) of2-[5-methoxymethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 123-124° C.

Reference Example 20

A mixture of2-[5-methoxymethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile(1.83 g), 10% sulfuric acid (5 mL) and tetrahydrofuran (50 mL) washeated under reflux for 3 hrs. Water was added to the reaction mixtureand the mixture was extracted with ethyl acetate. The organic layer waswashed successively with saturated aqueous sodium hydrogencarbonate andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated to give crystals (1.13 g, 68%) of2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 185-186° C.

Reference Example 21

A mixture of2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile(0.40 g), benzyl bromide (0.48 g), anhydrous potassium carbonate (0.14g) and N,N-dimethylformamide (5 mL) was stirred at 90° C. for 3 hrs. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed successively with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theobtained residue was subjected to silica gel column chromatography togive crystals (0.27 g, 55%) of2-[5-benzyloxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:4, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 130-131° C.

Reference Example 22

A mixture of methyl methylthiomethyl sulfoxide (11.7 g), 40% solution ofbenzyltrimethylammonium hydroxide in methanol (7.5 mL),5-chloro-2-methoxymethoxybenzaldehyde (9.43 g) and tetrahydrofuran (150mL) was heated under reflux for 20 hrs. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. A mixture of the obtained residue and 10%hydrogen chloride-methanol (100 mL) was heated under reflux for 15 hrs.The reaction mixture was concentrated, and ethyl acetate was added tothe residue. The organic layer was washed successively with water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (7.24 g, 91%) of methyl2-(5-chloro-2-hydroxyphenyl)acetate from a fraction eluted with ethylacetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexanegave colorless prism crystals. melting point: 84-85° C.

Reference Example 23

To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(4.52 g), methyl 5-hydroxy-3-pyridinecarboxylate (2.0 g), andN,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.58g) under ice-cooling, and the mixture was stirred at room temperaturefor 3 hrs. The reaction mixture was poured into water, and theprecipitated crystals were collected by filtration. The crystals weresubjected to silica gel column chromatography to give crystals (2.41 g,0.43%) of methyl5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarboxylatefrom a fraction eluted with ethyl acetate-hexane (1:1, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 138-139° C.

Reference Example 24

To a mixture of methyl5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarboxylate(2.09 g), sodium tetrahydroborate (0.93 g) and tetrahydrofuran (100 mL)was dropwise added methanol (10 mL) at 50° C., and the mixture wasstirred at 50° C. for 1 hr. To the reaction mixture was added water andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated to give crystals (1.85 g, 94%) of[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 128-130° C.

Reference Example 25

To a mixture of[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol(1.68 g), triethylamine (0.85 g) and ethyl acetate (100 mL) was dropwiseadded methanesulfonyl chloride (0.96 g) at room temperature, and themixture was stirred at room temperature for 15 hrs. The reaction mixturewas washed successively with water, saturated aqueous sodiumhydrogencarbonate, 1N hydrochloric acid and saturated brine, dried overanhydrous magnesium sulfate, and concentrated to give pale-yellowcrystals. To a mixture of the crystals and dimethyl sulfoxide (20 mL)was added an aqueous solution (2 mL) of sodium cyanide (0.41 g) at roomtemperature and the mixture was stirred at room temperature for 2 days.To the reaction mixture was added water and the mixture was extractedwith ethyl acetate. The organic layer was washed successively with waterand saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (0.76 g, 44%) of2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (2:1, v/v).Recrystallization from ethyl acetate-hexane gave pale-yellow prismcrystals. melting point: 137-138° C.

Reference Example 26

To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(4.52 g), 2-(2-hydroxy-1-naphthyl)acetonitrile (0.58 g) andN,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.14g) under ice-cooling, and the mixture was stirred at room temperaturefor 1 hr. To the reaction mixture was added water and the mixture wasextracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, dried over anhydrous magnesium sulfate,and concentrated. The obtained residue was subjected to silica gelcolumn chromatography to give crystals (1.11 g, 76%) of2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave pale-yellow prismcrystals. melting point: 178-179° C.

Reference Example 27

To a solution of2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-carbaldehyde (13.0 g)in tetrahydrofuran (150 ml)-methanol (10 ml) was gradually added sodiumborohydride (835 mg) at 0° C. After stirring for 30 min., water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with water, dried over anhydrousmagnesium sulfate, and concentrated to give crystals of2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-methanol.Recrystallization from acetone-isopropyl ether gave colorless prismcrystals (12.4 g, yield 95%). melting point: 121-122° C.

Reference Example 28

To a mixture of2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-methanol (12.2 g) andtoluene (200 ml) was added thionyl chloride (5.39 g), and the mixturewas stirred at room temperature for 1 hr. Iced water was added to thereaction mixture, and after neutralization with saturated aqueous sodiumhydrogencarbonate, the mixture was extracted with ethyl acetate. Theorganic layer was washed with water, dried over anhydrous magnesiumsulfate, and concentrated. The residue was subjected to silica gelcolumn chromatography to give crystals (11.7 g, yield 90%) of5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:86-87° C.

Reference Example 29

A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (13.4 g), methyl5-hydroxypyridine-3-carboxylate (9.84 g), anhydrous potassium carbonate(8.90 g) and N,N-dimethylformamide (100 mL) was stirred overnight at 80°C. The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (12.42 g, 59%) ofmethyl 5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridinecarboxylatefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 119-120° C.

Reference Example 30

To a mixture of methyl5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridinecarboxylate (10.70 g)and tetrahydrofuran (100 mL) was added lithium aluminum hydride (1.02 g)under ice-cooling, and the mixture was stirred at room temperature for10 min. To the mixture was added sodium sulfate 10 hydrate (8.38 g), andthe mixture was further stirred at room temperature for 30 min. Theinsoluble materials were removed by filtration, and the filtrate wasconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (8.93 g, 91%) of[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridyl]methanol from afraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:111-112° C.

Reference Example 31

A mixture of4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole-(2.76 g),2,4-dihydroxybenzophenone (2.00 g), anhydrous potassium carbonate (1.29g) and acetone (50 mL) was heated under reflux for 0.15 hrs. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated to give crystals (1.72 g, 40%) of4-[4-(4-benzoyl-3-hydroxyphenoxymethyl)phenoxymethyl]-5-methyl-2-phenyloxazole.Recrystallization from ethyl acetate-hexane gave pale-yellow prismcrystals. melting point: 160-161° C.

Reference Example 32

To a mixture of4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (3.23 g),tetrahydrofuran (15 ml) and methanol (15 mL) was added sodiumborohydride (0.378 g) at room temperature and the mixture was stirred atroom temperature for 30 min. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over an hydrous magnesium sulfate, andconcentrated to give crystals of[[4-methoxy-3(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol.Recrystallization from tetrahydrofuran-hexane gave pale-yellow platecrystals (3.22 g, 99%). melting point: 144-145° C.

Reference Example 33

To a mixture of 4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzaldehyde(37.8 g), tetrahydrofuran (140 ml) and methanol (60 mL) was added sodiumborohydride (2.53 g) under ice-cooling, and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was poured into icedwater, and the precipitated solid was collected by filtration, and driedwith air to give crystals (34.6 g, 91%) of[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 91-92° C.

Reference Example 34

To a mixture of[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanol (34.5 g),tetrahydrofuran (100 mL) and toluene (300 mL) was added thionyl chloride(17.3 g) under ice-cooling, and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was concentrated and theresidue was dissolved in ethyl acetate. The mixture was washedsuccessively with saturated aqueous sodium hydrogencarbonate and water,dried over anhydrous magnesium sulfate, and concentrated. The residuewas washed with diisopropyl ether to give colorless crystals (31.1 g,85%) of 4-(4-chloromethylphenoxymethyl)-2-(2-furyl)-5-methylthiazole.Recrystallization from ethyl acetate-diisopropyl ether gave colorlessprism crystals. melting point: 115-116° C.

Reference Example 35

To a mixture of 4-[(2-phenyl-4-thiazolyl)methoxy]benzaldehyde (6.35 g),tetrahydrofuran (30 ml) and methanol (20 mL) was added sodiumborohydride (0.45 g) under ice-cooling, and the mixture was stirred atroom temperature for 30 min. Dilute hydrochloric acid and water wereadded to acidify the reaction mixture. The precipitated solid wascollected by filtration, and dried with air to give crystals (5.76 g,90%) of [4-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless needlecrystals. melting point: 145-146° C.

Reference Example 36

To a mixture of [4-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.35g), tetrahydrofuran (50 mL) and toluene (50 mL) was added a solution (5mL) of thionyl chloride (1.5 mL) in toluene under ice-cooling, and themixture was stirred at room temperature for 2 hrs. The reaction mixturewas concentrated and the residue was dissolved in ethyl acetate. Themixture was washed successively with saturated aqueous sodiumhydrogencarbonate and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated to give colorless crystals (4.10 g, 89%) of4-(4-chloromethylphenoxymethyl)-2-phenylthiazole. melting point: 98-99°C.

Reference Example 37

A mixture of 4-chloromethyl-5-methyl-2-phenylthiazole (5.40 g),4-hydroxybenzaldehyde (2.91 g), anhydrous potassium carbonate (4.95 g)and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 3 hrs. Thereaction mixture was poured into water, and the precipitated solid wascollected by filtration, and dried with air to give crystals (6.85 g,93%) of 4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzaldehyde.Recrystallization from ethyl aceetate-hexane gave colorless prismcrystals. melting point: 18-119° C.

Reference Example 38

To a mixture of 4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzaldehyde(6.00 g), tetrahydrofuran (30 ml) and methanol (20 mL) was added sodiumborohydride (0.38 g) under ice-cooling, and the mixture was stirred atroom temperature for 30 min. Dilute hydrochloric acid and water wereadded to acidify the reaction mixture, and the precipitated solid wascollected by filtration, and dried with air to give crystals (5.68 g,94%) of [4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]phenyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 94-95° C.

Reference Example 39

To a mixture of[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.50 g),tetrahydrofuran (50 mL) and toluene (50 mL) was added a solution (5 mL)of thionyl chloride (1.5 mL) in toluene under ice-cooling, and themixture was stirred at room temperature for 2 hrs. The reaction mixturewas concentrated and the residue was dissolved in ethyl acetate. Themixture was washed successively with saturated aqueous sodiumhydrogencarbonate and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated to give colorless crystals (4.50 g, 94%) of4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenylthiazole. meltingpoint: 100-101° C.

Reference Example 40

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(11.13 g), 2-hydroxy-1-naphthaldehyde (5.96 g), anhydrous potassiumcarbonate (5.03 g) and N,N-dimethylformamide (50 mL) was stirred at roomtemperature for 2 days. The reaction mixture was poured into water, andthe precipitated solid was collected by filtration, and dried with airto give crystals (13.83 g, 89%) of2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthaldehyde.Recrystallization from ethyl acetate-hexane gave pale-yellow prismcrystals. melting point: 141-142° C.

Reference Example 41

A mixture of 5-methoxy-2-methoxymethoxybenzaldehyde (9.25 g), methylmethylthiomethyl sulfoxide (11.7 g), 40% solution ofbenzyltrimethylammonium hydroxide in methanol (10 mL) andtetrahydrofuran (200 mL) heated under reflux for 20 hrs. Water was addedto the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated. A mixture of the obtainedresidue and 10% hydrogen chloride-methanol (80 mL) was heated underreflux for 15 hrs. The reaction mixture was concentrated, and ethylacetate was added to the residue. The organic layer was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (4.88 g, 53%) ofmethyl 2-(2-hydroxy-5-methoxyphenyl)acetate from a fraction eluted withethyl acetate-hexane (1:4, v/v). Recrystallization from ethylacetate-hexane gave colorless prism crystals. melting point: 69-70° C.

Reference Example 42

A mixture of 2-benzyloxy-5-hydroxybenzaldehyde (8.93 g), ethyl iodide(7.31 g), anhydrous potassium carbonate (5.40 g) andN,N-dimethylformamide (50 mL) was stirred at room temperature for 15hrs. The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The obtained residue wassubjected to silica gel column chromatography to give2-benzyloxy-5-ethoxybenzaldehyde as a colorless oil (9.25 g, 92%) from afraction eluted with ethyl acetate-hexane (1:9, v/v).

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=7.0 Hz), 4.02 (2H, q, J=7.0 Hz), 5.14(2H, s), 6.96-7.13 (2H, m), 7.30-7.42 (6H, m), 10.50 (1H, s).

Reference Example 43

A mixture of methyl methylthiomethyl sulfoxide (1.94 g) and finelytriturated sodium hydroxide (0.01 g) was stirred at 70° C. for 30 min.2-Benzyloxy-5-ethoxybenzaldehyde (2.0 g) and methanol (10 mL) were addedto the reaction mixture, and the mixture was further heated under refluxfor 24 hrs. To the reaction mixture was added ethyl acetate, and theorganic layer was washed successively with 1N hydrochloric acid andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. A mixture of the obtained residue and 10% hydrogenchloride-methanol (100 mL) was heated under reflux for 24 hrs. Thereaction mixture was concentrated, and then ethyl acetate was added tothe residue. The organic layer was washed successively with saturatedaqueous sodium hydrogencarbonate and saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The obtained residue wassubjected to silica gel column chromatography to give methyl2-(2-benzyloxy-5-ethoxyphenyl)acetate as a yellow oil (1.60 g, 69%) froma fraction eluted with ethyl acetate-hexane (1:3, v/v).

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.0 Hz), 3.63 (3H, s), 3.65 (2H, s),3.98 (2H, q, J=7.0 Hz), 5.02 (2H, s), 6.73-6.87 (3H, m), 7.26-7.42 (5H,m).

Reference Example 44

A mixture of methyl 2-(2-benzyloxy-5-ethoxyphenyl)acetate (1.60 g), 5%palladium carbon (3.0 g) and tetrahydrofuran (50 mL) was subjected tocatalytic hydrogenation at room temperature and 1 atm. After filteringoff the catalyst, the solvent was evaporated under reduced pressure.Hexane was added to the obtained crystals and the mixture was filtratedto give crystals (0.82 g) of methyl 2-(2-hydroxy-5-ethoxyphenyl)acetate.Recrystallization from diisopropyl ether-hexane gave pale-yellow prismcrystals. melting point: 83-84° C.

Reference Example 45

To a mixture of triethyl phosphonoacetate (3.86 g),2-benzyloxy-5-ethoxybenzaldehyde (2.00 g) and N,N-dimethylformamide (100mL) was added sodium hydride (60%, oil, 0.75 g) under ice-cooling. Thereaction mixture was stirred at room temperature for 3 hrs. Water wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed successively with water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give ethyl(E)-3-(2-benzyloxy-5-ethoxyphenyl)-2-propenoate as a colorless oil (4.58g, 90%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 1.33 (3H, t, J=7.0 Hz), 1.39 (3H, t, J=7.0 Hz), 3.99(2H, q, J=7.0 Hz), 4.25 (2H, q, J=7.0 Hz), 5.10 (2H, s), 6.48 (1H, d,J=16.0 Hz), 6.85-6.91 (2H, m), 7.06-7.08 (1H, m), 7.25-7.44 (5H, m),8.06 (1H, d, J=16.0 Hz),

Reference Example 46

A mixture of ethyl (E)-3-(2-benzyloxy-5-ethoxyphenyl)-2-propenoate (4.58g), 5% palladium carbon (6.0, g) and tetrahydrofuran (100 mL) wassubjected to catalytic hydrogenation at room temperature and 1 atm.After filtering off the catalyst, the solvent was evaporated underreduced pressure. The obtained residue was subjected to silica gelcolumn chromatography to give ethyl3-(5-ethoxy-2-hydroxyphenyl)propionate as a colorless oil (3.15 g, 94%)from a fraction eluted with ethyl acetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.0 Hz), 1.37 (3H, t, J=7.0 Hz),2.66-2.73 (2H, m), 2.82-2.89 (2H, m), 3:96 (2H, q, J=7.0 Hz), 4.14 (2H,q, J=7.0 Hz), 6.64-6.69 (2H, m), 6.77-6.84 (2H, m).

Reference Example 47

To a mixture of[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (10.0 g),2-chloro-3-cyanopyridine (4.27 g) and N,N-dimethylformamide (100 mL) wasadded sodium hydride (60%, oil, 1.48 g) under ice-cooling. The reactionmixture was stirred at room temperature for 15 hrs. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (10.98 g, 90%) of3-cyano-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]pyridinefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless needlecrystals. melting point: 119-120° C.

Reference Example 48

To a mixture of3-cyano-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]pyridine(8.42 g) and anhydrous toluene (300 mL) was dropwise added a solution(1M, 46.6 mL) of diisobutylaluminum hydride in hexane at −78° C. Thereaction mixture was allowed to warm to room temperature over 1 hr withstirring. A saturated aqueous ammonium chloride solution (70 L) wasdropwise added to the mixture, and the mixture was further stirred atroom temperature for 30 min. Ethyl acetate (300 mL) was added to themixture and, after stirring the mixture at room temperature for 30 min.,insoluble materials were filtered off. The filtrate, was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (6.49 g, 76%) of2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarbaldehydefrom a fraction eluted with ethyl acetate-hexane (1:4, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 97-98° C.

Reference Example 49

To a mixture of2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarbaldehyde(0.40 g), ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodiumborohydride (0.04 g) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. Water was added to the reaction mixture, and theprecipitated solid was collected by filtration, and dried with air togive crystals (0.35 g, 88%) of[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 139-140° C.

Reference Example 50

To a mixture of[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol(1.50 g), triethylamine (0.75 g) and ethyl acetate (150 mL) was dropwiseadded methanesulfonyl chloride (0.85 g) at room temperature and themixture was stirred at room temperature for 15 hrs. The reaction mixturewas washed successively with water, saturated aqueous sodiumhydrogencarbonate and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated to give an oil. A mixture of this oil, sodiumcyanide (0.72 g), benzyltributylammonium chloride (0.59 g), acetonitrile(20 mL) and water (10 ml) was stirred at room temperature for 15 hrs.The reaction mixture was concentrated, and ethyl acetate was added tothe residue. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The obtained residuewas subjected to silica gel column chromatography to give crystals (0.55g, 36%) of2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:4, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 149-150° C.

Reference Example 51

To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.97 g) methyl 3-hydroxypyridine 2-carboxylate (0.40 g), andN,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.12g) under ice-cooling. The reaction mixture was stirred at roomtemperature for 15 hrs. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give methyl3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]pyridine-2-carboxylateas a colorless oil (0.32 g, 29%) from a fraction eluted with ethylacetate-hexane (2:3, v/v).

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 3.98 (3H, s), 5.00 (2H, s), 5.16 (2H,s), 7.01-7.06 (2H, m), 7.36-7.47 (7H, m), 7.99-8.04 (2H, m), 8.28 (1H,t, J=3.2 Hz).

Reference Example 52

To a mixture of methyl3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridinecarboxylate(0.30 g), sodium borohydride (0.13 g) and tetrahydrofuran (10 mL) wasdropwise added methanol (2 mL) at 50° C., and the mixture was stirred at50° C. for 1 hr. To the reaction mixture was added water and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated to give crystals (0.23 g, 82%) of[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 118-119° C.

Reference Example 53

To a mixture of[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]methanol(0.74 g), triethylamine (0.36 g) and ethyl acetate (50 mL) was dropwiseadded methanesulfonyl chloride (0.41 g) at room temperature and themixture was stirred at room temperature for 14 hrs. The reaction mixturewas washed successively with water saturated aqueous sodiumhydrogencarbonate, 1N hydrochloric acid and saturated brine, dried overanhydrous magnesium sulfate, and concentrated to give a yellow oil. To amixture of this yellow oil and dimethyl sulfoxide (20 mL) was added anaqueous solution (2 mL) of sodium cyanide (0.18 g) at room temperatureand the mixture was stirred at room temperature for 2 days. Water wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed successively with water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (0.60 g, 81%) of2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:1, v/v).Recrystallization from ethyl acetate-hexane gave pale-brown prismcrystals. melting point: 138-139° C.

Reference Example 54

To a mixture of (5-methyl-2-phenyl-4-oxazolyl)methanol (9.46 g) andN,N-dimethylformamide (0.50 mL) was added sodium hydride (60%, oil, 2.40g) at room temperature and the reaction mixture was stirred at roomtemperature until generation of hydrogen ended. The mixture was added toa solution of methyl 2-chloropyridine-4-carboxylate (8.58 g) intetrahydrofuran (50 ml) at room temperature and the resulting mixturewas further stirred at room temperature for 1 hr. Water was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theorganic layer was washed successively with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The obtainedresidue was subjected to silica gel column chromatography to givecrystals of methyl2-(5-methyl-2-phenyl-4-oxazolyl)methoxy-4-pyridinecarboxylate from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless needle crystals (2.19 g, 14%).melting point: 106-107° C.

Reference Example 55

To a mixture of methyl2-(5-methyl-2-phenyl-4-oxazolyl)methoxy-4-pyridinecarboxylate (1.95 g)and tetrahydrofuran (20 mL) was added lithium aluminum hydride (0.228 g)under ice-cooling, and the mixture was stirred at room temperature for30 min. Sodium sulfate 10 hydrate (1.93 g) was added to the mixture andthe mixture was stirred at room temperature for 30 min. The insolublematerials were removed by filtration, and the filtrate was concentrated.The obtained crystals were recrystallized from ethyl acetate-hexane togive [2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridyl]methanol ascolorless plate crystals (1.37 g, 77%). melting point: 100-101° C.

Reference Example 56

To thionyl chloride (4 mL) was added[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridyl]methanol (1.19 g)under ice-cooling, and the mixture was stirred at room temperature for 1hr. The reaction mixture was concentrated, and saturated aqueous sodiumhydrogencarbonate was added to the residue. The mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The obtainedresidue was subjected to silica gel column chromatography to givecrystals of4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless needle crystals (0.68 g, 54%).melting point: 104-105° C.

Reference Example 57

To a mixture of (5-methyl-2-phenyl-4-oxazolyl)methanol (8.51 g) andtetrahydrofuran (100 mL) was added sodium hydride (60%, oil, 1.80 g) atroom temperature and the reaction mixture was stirred at roomtemperature until generation of hydrogen ended. The mixture was added toa solution of methyl 6-chloropyridine-2-carboxylate (7.72 g) intetrahydrofuran (75 ml) at room temperature and the obtained mixture wasfurther stirred at 40° C. for 5 hrs. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed successively with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The obtained residue wassubjected to silica gel column chromatography to give crystals of methyl6-(5-methyl-2-phenyl-4-oxazolyl)methoxy-2-pyridinecarboxylate from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave pale-yellow plate crystals (7.41 g, 51%).melting point: 97-98° C.

Reference Example 58

To a mixture of methyl6-(5-methyl-2-phenyl-4-oxazolyl)methoxy-2-pyridinecarboxylate (6.49 g)and tetrahydrofuran (60 mL) was added lithium aluminum hydride (0.759 g)under ice-cooling, and the mixture was stirred at room temperature for30 min. To the mixture was added sodium sulfate 10 hydrate (6.44 g) andfurther stirred at room temperature for 30 min. The insoluble materialswere removed by filtration, and the filtrate was concentrated to givecrystals. The obtained crystals were added to thionyl chloride (20 mL)under ice-cooling, and the mixture was stirred at room temperature for 1hr. The reaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The obtainedresidue was subjected to silica gel column chromatography to givecrystals of2-chloromethyl-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless plate crystals (2.74 g, 44%).melting point: 85-86° C.

Reference Example 59.

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.79 g), methyl 2-(5-hydroxy-2-propylphenoxy)acetate (1.17 g),anhydrous potassium carbonate (0.72 g) and N,N-dimethylformamide (50 mL)was stirred at 90° C. for 2 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (1.60 g, 61%) of methyl2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]acetatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 100-101° C.

Reference Example 60

To a mixture of methyl2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]acetate(1.16 g), tetrahydrofuran (4 mL) and methanol (4 mL) was added 1Naqueous sodium hydroxide solution (4.5 mL) and the mixture was stirredat room temperature for 2 hrs. 1N Hydrochloric acid and water were addedto acidify the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated to give crystals(1.01 g, 90%) of2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 162-163° C.

Reference Example 61

To a mixture of4-[4-(4-benzoyl-3-hydroxyphenoxymethyl)phenoxymethyl]-5-methyl-2-phenyloxazole(1.52 g) and N,N-dimethylformamide (20 mL) was added sodium hydride(60%, oil, 0.14 g) under ice-cooling, and the mixture was stirred atroom temperature for 1 hr. Methyl bromoacetate (0.57 g) was added to themixture and the mixture was stirred at 80° C. for 2 hrs., The reactionmixture was poured into water, and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. After concentration of the organic layer, the residuewas subjected to silica gel column chromatography to give methyl2-[2-benzoyl-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenoxy]acetateas an oil (1.65 g, 94%) from a fraction eluted with ethyl acetate-hexane(1:2, v/v).

¹H-NMR(CDCl₃)δ: 2.45 (3H, s), 3.68 (3H, s), 4.50 (2H, s), 5.02 (2H, s),5.03 (2H, s), 6.45 (1H, d, J=2.2 Hz), 6.69 (1H, dd. J=8.4, 2.2 Hz),7.03-7.08 (2H, m), 7.35-7.57 (9H, m), 7.80-7.84 (2H, m), 7.99-8.05 (2H,m).

Reference Example 62

To a mixture of methyl2-[2-benzoyl-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenoxy]acetate(0.55 g), tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was added a 1Naqueous sodium hydroxide solution (1.5 mL) and the mixture was stirredat room temperature for 3 hrs. 1N Hydrochloric acid and water were addedto acidify the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated to give2-[2-benzoyl-5-[4[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenoxy]aceticacid as a colorless amorphous compound (0.41 g, 76%).

¹H-NMR(CDCl₃)δ: 2.45 (3H, s), 4.76 (2H, s), 5.03 (2H, s), 5.08 (2H, s),6.63-6.70(2H, m), 7.04-7.08 (2H, m), 7.34-7.66 (9H, m), 7.79-7.83 (2H,m), 7.98-8.04 (2H, m).

Reference Example 63

A mixture of 2-hydroxy-4-methoxymethoxybenzaldehyde (17.1 g), benzylbromide (19.33 g), anhydrous potassium carbonate (13.0 g) andN,N-dimethylformamide (200 mL) was stirred at room temperature for 15hrs. The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue wassubjected to silica gel column chromatography to give2-benzyloxy-4-methoxymethoxybenzaldehyde as a colorless oil (25.3 g,99%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).

¹H-NMR(CDCl₃)δ: 3.48 (3H, s), 5.17 (2H, s), 5.21 (2H, s), 6.66-6.72 (2H,m), 7.34-7.47 (5H, m), 7.80-7.84 (1H, m), 10.40 (1H, s).

Reference Example 64

To a mixture of triethyl phosphonoacetate (10.9 g),2-benzyloxy-4-methoxymethoxybenzaldehyde (12.0 g) andN,N-dimethylformamide (150 mL) was added sodium hydride (60%, oil, 2.12g) under ice-cooling. The reaction mixture was stirred at roomtemperature for 13 hrs. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give ethyl(E)-3-(2-benzyloxy-4-methoxymethoxyphenyl)-2-propenoate as a colorlessoil (14.80 g, 98%) from a fraction eluted with ethyl acetate-hexane(1:4, v/v).

¹H-NMR(CDCl₃)δ: 1.32 (3H, t, J=7.0 Hz), 3.45 (3H, s), 4.23 (2H, q, J=7.4Hz), 5.15 (2H, s), 5.16 (2H, s), 6.44 (1H, d, J=16.0 Hz), 6.62-6.68 (2H,m), 7.24-7.49 (6H, m), 8.01 (1H, d, J=16.0 Hz).

Reference Example 65

A mixture of ethyl(E)-3-(2-benzyloxy-4-methoxymethoxyphenyl)-2-propenoate (14.80 g), 5%palladium carbon (20.0 g) and ethanol (300 mL) was subjected tocatalytic hydrogenation at room temperature and 1 atm. After filteringoff the catalyst, the solvent was evaporated under reduced pressure togive ethyl 3-(2-hydroxy-4-methoxymethoxyphenyl)propionate as a colorlessoil (9.17 g, 84%).

¹H-NMR(CDCl₃)δ: 1.24 (3H, t, J=7.0 Hz), 2.63-2.71 (2H, m), 2.79-2.86(2H, m), 3.46 (3H, s), 4.15 (2H, q, J=7.0 Hz), 5.13 (2H, s), 6.53-6.62(2H, m), 6.97 (1H, d, J=8.0 Hz), 7.43 (1H, brs).

Reference Example 66

A mixture of ethyl 3-(2-hydroxy-4-methoxymethoxyphenyl)propionate (6.00g), ethyl iodide (5.52 g), anhydrous potassium carbonate (3.26 g) andN,N-dimethylformamide (50 mL) was stirred at room temperature for 13hrs. The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated to give an oil. A mixtureof the obtained oil, 10% aqueous sulfuric acid solution (10 mL) andethanol (300 mL) was stirred with heating under reflux for 6 hrs. Thereaction mixture was concentrated under reduced pressure and the residuewas diluted with water, and then basified with a saturated aqueoussodium hydrogencarbonate. The mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give ethyl3-(2-ethoxy-4-hydroxyphenyl)propionate as a colorless oil (3.58 g, 64%)from a fraction eluted with ethyl acetate-hexane (1:6, v/v).

¹H-NMR(CDCl₃)δ: 1.23 (3H, t, J=7.0 Hz), 1.41 (3H, t, J=7.0 Hz),2.52-2.61 (2H, m), 2.81-2.89 (2H, m), 3.98 (2H, q, J=7.0 Hz), 4.12 (2H,q, J=7.0 Hz), 5.00 (1H, brs), 6.26-6.37 (2H, m), 6.96 (1H, d, J=8.2 Hz).

Reference Example 67

To a mixture of[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (1.92 g),methyl 5-hydroxynicotinate (1.0 g), tributylphosphine (1.98 g) andtetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine(2.47 g) at room temperature and the mixture was stirred for 15 hrs. Theprecipitated crystals were removed by filtration. The filtrate wasconcentrated and the residue was subjected to silica gel columnchromatography to give crystals (2.21 g, 79%) of methyl5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinate from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:96-97° C.

Reference Example 68

To a mixture ofmethyl-5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinate(0.50 g) and tetrahydrofuran (10 mL) was added lithium aluminum hydride(0.045 g) under ice-cooling, and the mixture was stirred at roomtemperature for 3 hrs. Sodium sulfate 1.0 hydrate (0.39 g) was added tothe mixture and the mixture was further stirred at room temperature for30 min. The insoluble materials were removed by filtration, and thefiltrate was concentrated to give crystals (0.47 g, 98%) of[5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless needlecrystals. melting point: 145-146° C.

Reference Example 69

To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (3.51 g) inN,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 1.07g) at 0° C. After stirring for 30 min.,4-chloromethyl-5-methyl-2-phenylthiazole (5.00 g) was added. Afterstirring at 60° C. for 2 hrs, the reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The residue was subjected to silicagel column chromatography to give methyl3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolecarboxylate (5.42 g,74%) as colorless crystals from a fraction eluted with ethylacetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexanegave colorless prism crystals. melting point: 89-90° C.

Reference Example 70

A mixture of[5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol(4.60 g), thionyl chloride (1.7 mL) and toluene (50 mL) was stirred at100° C. for 1 hr. The reaction mixture was concentrated, and then ethylacetate was added. The mixture was washed successively with saturatedaqueous sodium hydrogencarbonate and saturated brine, and then the ethylacetate layer was dried over anhydrous magnesium sulfate andconcentrated. Sodium cyanide (0.91 g), 18-crown-6 (0.35 g) andacetonitrile (50 mL) were added to the residue and the mixture washeated under reflux for 2.5 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography to give2-[5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrileas a pale-brown oil (3.06 g, 65%) from a fraction eluted withtetrahydrofuran-hexane (1:1, v/v).

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 3.73 (2H, s), 5.01 (2H, s), 5.13 (2H,s), 6.96-7.14 (3H, m), 7.22-7.52 (5H, m), 7.74-8.07 (2H, m), 8.18 (1H,d, J=2.0 Hz), 8.35 (1H, d, J=2.6 Hz).

Reference Example 71

To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g) inN,N-dimethylformamide (70 mL) was added sodium hydride (60%, oil, 1.40g) at 0° C. and, after stirring the mixture for 15 min.,4-chloromethyl-5-methyl-2-phenyloxazole (7.26 g) was added. Afterstirring the mixture at 60° C. for 2 hrs., the reaction mixture waspoured into water and extracted with ethyl acetate. The ethyl acetatelayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was subjected to silica gel columnchromatography to give methyl3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolecarboxylate (7.96 g,yield 72%) as colorless crystals from a fraction eluted withtetrahydrofuran-hexane (1:1, v/v). The crystals were recrystallized fromtetrahydrofuran-hexane. melting point: 123-124° C.

Reference Example 72

To a solution of methyl3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolecarboxylate (7.86 g)in tetrahydrofuran (150 mL) was slowly added diisobutylaluminum hydride(1.0 M tetrahydrofuran solution, 60 mL) at 0° C. and the mixture wasstirred at room temperature for 30 min. The reaction mixture was pouredinto dilute hydrochloric acid and extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated to give3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (5.93 g,yield 86%) as colorless crystals. The crystals were recrystallized fromethyl acetate-hexane. melting point: 99-100° C.

Reference Example 73

To a solution of3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (2.86 g) intoluene (50 ml) was slowly added thionyl chloride (0.80 mL) at roomtemperature and the mixture was stirred under reflux for 30 min. Aftercooling, the reaction mixture was poured into saturated aqueous sodiumhydrogencarbonate and extracted with ethyl acetate. The ethyl acetatelayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated to give5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (2.70 g,yield 89%) as colorless crystals. The crystals were recrystallized fromethyl acetate-hexane. melting point: 105-106° C.

Reference Example 74

To a mixture of 5-formyl-2-hydroxybenzoic acid (15.34 g) andN,N-dimethylformamide (150 mL) was added sodium hydride (60%, oil, 9.24g) under ice-cooling. The reaction mixture was stirred at roomtemperature for 30 min., and then chloromethyl methyl ether (29.7 g) wasadded to the reaction mixture under ice-cooling. The reaction mixturewas further stirred at room temperature for 15 hrs. The reaction mixturewas poured into water and extracted with ethyl acetate. The organiclayer was washed successively with water and saturated brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue wassubjected to silica gel column chromatography to give methoxymethyl5-formyl-2-methoxymethoxybenzoate as a colorless oil (14.23 g, 61%) froma fraction eluted with ethyl acetate-hexane (2:3, v/v).

¹H-NMR (CDCl₃) δ: 3.52 (3H, s), 3.57 (3H, s), 5.36 (2H, s), 5.48 (2H,s), 7.32-7.37 (1H, m), 7.96-8.04 (1H, m), 8.33-8.37 (1H, m), 9.93 (1H,s).

To a mixture of dimethyl sulfoxide (100 mL) and tetrahydrdfuran (300 mL)was added sodium hydride (60%, oil, 3.58 g) at room temperature. Thereaction mixture was stirred at 50° C. for 1.5 hrs. The reaction mixturewas allowed to warm to room temperature, and then ethyltriphenylphosphonium bromide (27.03 g) was added. The mixture wasstirred at room temperature for 30 min. To the reaction mixture wasadded a solution (50 mL) of methoxymethyl5-formyl-2-methoxymethoxybenzoate (14.23 g) in dimethyl sulfoxide andthe mixture was heated under reflux for 1 hr. Water was added to thereaction mixture, and the mixture was neutralized with 1N hydrochloricacid and extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give a colorless oil from a fraction eluted with ethylacetate-hexane (1:8, v/v). A mixture of the obtained oil, 5% palladiumcarbon (7.0 g) and tetrahydrofuran (300 mL) was subjected to catalytichydrogenation at room temperature and 1 atm. After filtering off thecatalyst, the solvent was evaporated under reduced pressure to givemethyl 2-methoxymethoxy-5-propylbenzoate as an oil (6.06 g, 45%).

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.2 Hz), 1.52-1.72 (2H, m), 2.55 (2H,t, J=7.6 Hz), 3.52 (3H, s), 3.89 (3H, s), 5.22 (2H, s), 7.10 (1H, d,J=8.4 Hz), 7.25 (1H, dd, J=8.4, 2.2 Hz), 7.59 (1H, d, J=2.2 Hz).

To a mixture of methyl 2-methoxymethoxy-5-propylbenzoate (6.06 g) andtetrahydrofuran (200 mL) was added lithium aluminum hydride (0.96 g)under ice-cooling, and the mixture was stirred at room temperature for 1hr. To the mixture was added sodium sulfate 10 hydrate (8.18 g) and themixture was further stirred at room temperature for 30 min. Theinsoluble materials were removed by filtration, and the filtrate wasconcentrated to give (2-methoxymethoxy-5-propylphenyl)methanol as an oil(4.98 g, 93%).

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.2 Hz), 1.55-1.71 (2H, m), 2.28 (1H,t, J=6.4 Hz), 2.53 (2H, t, J=7.4 Hz), 3.49 (3H, s), 4.68 (2H, d, J=6.4Hz), 5.21 (2H, s), 6.98-7.11 (3H, m).

A mixture of (2-methoxymethoxy-5-propylphenyl)methanol (4.98 g),activated manganese dioxide (15.0 g) and ethyl acetate (300 ml) wasstirred at room temperature for 15 hrs. Manganese dioxide was removed byfiltration and the filtrate was concentrated. The obtained residue wassubjected to silica gel column chromatography to give2-methoxymethoxy-5-propylbenzaldehyde as an oil (4.19 g, 85%) from afraction eluted with ethyl acetate-hexane (1:4, v/v).

¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J=7.2 Hz), 1.52-1.68 (2H, m), 2.56 (2H,t, J=7.4 Hz), 3.52 (3H, s), 5.28 (2H, s), 7.13 (1H, d, J=8.8 Hz), 7.35(1H, dd, J=8.8, 2.2 Hz), 7.65 (1H, d, J=2.2 Hz), 10.49 (1H, s).

A mixture of 2-methoxymethoxy-5-propylbenzaldehyde (4.15 g), methylmethylthiomethyl sulfoxide (4.94 g), 40% solution ofbenzyltrimethylammonium hydroxide in methanol (4 mL) and tetrahydrofuran(100 mL) was heated under reflux for 24 hrs.

Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated. A mixture ofthe obtained residue and 10% hydrogen chloride-methanol (100 mL) washeated under reflux for 15 hrs. The reaction mixture was concentrated,and ethyl acetate was added to the residue. The organic layer was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (1.65 g, 40%) ofmethyl 2-(2-hydroxy-5-propyl)phenylacetate from a fraction eluted withethyl acetate-hexane (1:6, v/v). Recrystallization from isopropylether-hexane gave colorless prism crystals. melting point: 74-75° C.

Reference Example 75

To a mixture of (2-phenyl-4-oxazolyl)methanol (15.60 g) andtetrahydrofuran (300 mL) was added sodium hydride (60%, oil, 4.28 g)under ice-cooling, and the mixture was stirred at room temperature for 1hr. Chloromethyl methyl ether (9.34 g) was added to the reaction mixtureunder ice-cooling, and the mixture was stirred at room temperature for15 hrs. To the reaction mixture was added water and the mixture wasextracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, dried over anhydrous magnesium sulfateand concentrated. The obtained residue was subjected to silica gelcolumn chromatography to give 4-methoxymethoxymethyl-2-phenyloxazole asa colorless oil (10.86 g, 56%) from a fraction eluted with ethylacetate-hexane (1:8, v/v).

¹H-NMR (CDCl₃) δ: 3.44 (3H, s), 4.60 (2H, s), 4.76 (2H, s), 7.41-7.49(3H, m), 7.68 (1H, s), 8.01-8.08 (2H, m).

To a mixture of 4-methoxymethoxymethyl-2-phenyloxazole (10.86 g) anddiethyl ether (300 mL) was dropwise added a solution (1.6 M, 37 mL) ofn-butyl lithium in hexane at −78° C., and the mixture was stirred at−78° C. for 1.5 hrs. A solution (10 mL) of N,N-dimethylformamide (6.50g) in diethyl ether was added to the reaction mixture and the reactionmixture was allowed to warm to room temperature with stirring for 2 hrs.Dilute hydrochloric acid was added to the reaction mixture and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (6.45 g, 53%) of4-methoxymethoxymethyl-2-phenyl-5-oxazolecarbaldehyde from a fractioneluted with ethyl acetate-hexane (1:6, v/v). Recrystallization fromethyl acetate-hexane gave colorless prism crystals. melting point:51-52° C.

To a mixture of dimethyl sulfoxide (80 mL) and tetrahydrofuran (200 mL)was added sodium hydride (6.0%, oil, 1.81 g) at room temperature and themixture was stirred at 50° C. for 1.5 hrs. After allowing the reactionmixture to cool to room temperature, ethyl triphenylphosphonium bromide(13.66 g) was added and the mixture was stirred at room temperature for30 min. A solution (20 mL) of4-methoxymethoxymethyl-2-phenyl-5-oxazolecarbaldehyde (7.0 g) indimethyl sulfoxide was added to the reaction mixture and the mixture washeated under reflux for 1 hr. Water was added to the reaction mixture,and the mixture was neutralized with 1N hydrochloric acid and extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The obtainedresidue was subjected to silica gel column chromatography to give an oilfrom a fraction eluted with ethyl acetate-hexane (1:6, v/v). A mixtureof the obtained oil, 5% palladium carbon (2.0 g) and tetrahydrofuran(200 mL) was subjected to catalytic hydrogenation at room temperatureand 1 atm. After filtering off the catalyst, the solvent was evaporatedunder reduced pressure to give4-methoxymethoxymethyl-2-phenyl-5-propyloxazole as a colorless oil (2.65g, 36%).

¹H-NMR (CDCl₃) δ: 1.00 (3H, t, J=7.2 Hz), 1.64-1.83 (2H, m), 2.73 (2H,t, J=7.2 Hz), 3.43 (3H, s), 4.52 (2H, s), 4.74 (2H, s), 7.39-7.49 (3H,m), 7.98-8.05 (2H, m).

A mixture of 4-methoxymethoxymethyl-2-phenyl-5-propyloxazole (2.64 g),10% sulfuric acid (10 mL) and tetrahydrofuran (100 mL) was heated underreflux for 24 hrs. To the reaction mixture was added ethyl acetate, andthe mixture was washed successively with water and saturated brine,dried over anhydrous magnesium sulfate and concentrated to give(2-phenyl-5-propyl-4-oxazolyl)methanol as a colorless oil (2.10 g, 96%).

¹H-NMR (CDCl₃) δ: 0.99 (3H, t, J=7.4 Hz), 1.63-1.82 (2H, m), 2.71 (2H,t, J=7.4. Hz), 3.00 (1H, brs), 4.60 (2H, s), 7.39-7.50 (3H, m),7.95-8.04 (2H, m).

Reference Example 76

To a mixture of 2-phenyl-5-propyl-4-oxazolylmethanol (1.38 g) andtoluene (100 mL) was added thionyl chloride (1.38 g) under ice-cooling,and the mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated and the residue was dissolved in ethyl acetate.The mixture was washed successively with saturated aqueous sodiumhydrogencarbonate and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated to give4-chloromethyl-2-phenyl-5-propyloxazole as a colorless oil (2.26 g,99%).

¹H-NMR (CDCl₃) δ: 1.01 (3H, t, J=7.2 Hz), 1.66-1.85 (2H, m), 2.73 (2H,t, J=7.2 Hz), 4.56 (2H, s), 7.42-7.46 (3H, m), 7.99-8.04 (2H, m).

Reference Example 77

A mixture of 4-chloromethyl-2-phenyl-5-propyloxazole (2.26 g),4-hydroxybenzaldehyde (1.33 g), anhydrous potassium carbonate (1.76 g)and N,N-dimethylformamide (50 mL) was stirred at 60° C. for 4 hrs. Thereaction mixture was poured into water, and the precipitated solid wascollected by filtration and dried with air to give crystals (2.75 g,89%) of 4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzaldehyde.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 76-77° C.

Reference Example 78

To a mixture of 4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzaldehyde(2.40 g), tetrahydrofuran (30 ml) and ethanol (10 mL) was added sodiumborohydride (0.28 g) at room temperature and the mixture was stirred atroom temperature for 1 hr. To, the reaction mixture was added water andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (1.60 g, 66%) of[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]phenyl]methanol from afraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:79-80° C.

Reference Example 79

To a mixture of[6-(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethanol (4.01 g),2-chloro-3-cyanopyridine (1.79 g) and N,N-dimethylformamide (50 mL) wasadded sodium hydride (60%, oil, 0.62 g) under ice-cooling. The reactionmixture was stirred at room temperature for 3 hrs. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (4.72 g, 92%) of2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]nicotinonitrilefrom a fraction eluted with ethyl acetate-hexane (1:4, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 117-118° C.

Reference Example 80

To a mixture of2′-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]nicotinonitrile(4.53 g) and anhydrous toluene (100 mL) was dropwise added a solution(0.95 M, 26.3 mL) of diisobutylaluminum hydride in hexane at −78° C. Thereaction mixture was allowed to warm to room temperature with stirringfor 1 hr. An aqueous solution (50 mL) of saturated ammonium chloride wasdropwise added to the mixture and the mixture was further stirred atroom temperature for 15 min. To the mixture was added ethyl acetate andthe mixture was stirred at room temperature for 30 min., and then theinsoluble materials were filtered off. The filtrate was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]nicotinaldehydeas a colorless oil (3.17 g, 69%) from a fraction eluted with ethylacetate-hexane (1:2, v/v).

¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 5.31 (2H, s), 5.48 (2H, s), 6.85 (1H, d,J=8.4 Hz), 7.01-7.07 (1H, m), 7.39-7.46 (3H, m), 7.73 (1H, dd, J=8.4,2.6 Hz), 8.01-8.05 (2H, m), 8.14 (1H, dd, J=7.2, 2.0 Hz), 8.31 (1H, d,J=2.6 Hz), 8.40 (1H, dd, J=4.6, 2.0 Hz), 10.38 (1H, d, J=0.8 Hz).

Reference Example 81

To a mixture of2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]nicotinaldehyde(3.16 g), tetrahydrofuran (50 ml) and ethanol (50 mL) was added sodiumborohydride (0.30 g) at 0° C. and the mixture was stirred at roomtemperature for 30 min. Water was added to the reaction mixture, and theprecipitated solid was collected by filtration, and dried with air togive crystals (2.70 g, 85%) of[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methxy]-3-pyridyl]methoxy]-3-pyridyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 142-143° C.

Reference Example 82

To a mixture of[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]methanol(2.55 g), triethylamine (1.27 g) and ethyl acetate (200 mL) was dropwiseadded methanesulfonyl chloride (1.44 g) under ice-cooling and themixture was stirred at room temperature for 3 hrs. The reaction mixturewas washed successively with water, saturated aqueous sodiumhydrogencarbonate and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated to give an oil. To a mixture of this oil anddimethyl sulfoxide (30 mL) was added an aqueous solution (3 mL) ofsodium cyanide (0.77 g) at room temperature and the mixture was stirredat room temperature for 15 hrs. To the reaction mixture was added waterand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (1.85 g, 71%) of2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 110-111° C.

Reference Example 83

To a mixture of 2-(2-furyl)-5-methyl-4-oxazolylmethanol (10.8 g), methyl2-chloro-4-pyridinecarboxylate (10.3 g) and a solution oftetrahydrofuran (100 mL) and N,N-dimethylformamide (100 mL) was addedsodium hydride (60%, oil, 2.88 g) at 0° C. and the mixture was stirredat room temperature for 2 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography to give ethyl2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridinecarboxylate (2.86g, yield 15%) as colorless crystals from a fraction eluted with ethylacetate-hexane (1:3, v/v). The crystals were recrystallized from ethylacetate-hexane. melting point: 80-81.

Reference Example 84

To a solution of ethyl2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridinecarboxylate (2.63g) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (304mg) at 0° C. and the mixture was stirred at room temperature for 30 min.Sodium sulfate 10 hydrate (2.58 g) was added to the reaction mixture andthe mixture was stirred at room temperature for 30 min. The precipitatewas filtered off by filtration and the filtrate was concentrated. Amixture of the residue, thionyl chloride (10 mL) and toluene (5 mL) wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated, and then saturated aqueous sodium hydrogencarbonate wasadded to the mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated. The residue was subjectedto silica gel column chromatography to give4-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (1.02g, yield 42%) as colorless crystals from a fraction eluted with ethylacetate-hexane (1:3, v/v). The crystals were recrystallized from ethylacetate-hexane. melting point: 107-108° C.

Reference Example 85

To a mixture of3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl alcohol (4.00g), 2-chloro-3-cyanopyridine (1.62 g) and N,N-dimethylformamide (40 mL)was added sodium hydride (60%, oil, 515 mg) under ice-cooling. Thereaction mixture was stirred at room temperature for 15 hrs. Water wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The obtained crystalswere recrystallized from ethyl acetate-hexane to give2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrileas pale-yellow crystals (4.50 g, 90%). melting point: 117-118° C.

Reference Example 86

To a mixture of2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrile(4.25 g) and toluene (150 mL) was dropwise added a solution (0.95 M,23.0 mL) of diisobutylaluminum hydride in hexane at −78° C. Afterstirring for 1 hr the reaction mixture was warmed to room temperatureand the mixture was further stirred for 1 hr. A saturated aqueousammonium chloride solution (35 mL) was dropwise added to the mixture andthe mixture was stirred at room temperature for 30 min. To the mixturewas added ethyl acetate and the insoluble materials were filtered off.The filtrate was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated. The obtained residue was subjectedto silica gel column chromatography to give2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehydeas crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless crystals (710mg, 17%). melting point: 99-100° C.

Reference Example 87

To a mixture of2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehyde(620 mg), tetrahydrofuran (10 ml) and ethanol (10 mL) was added sodiumborohydride (54 mg) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. To the reaction mixture was added water and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated to give crystals (615 mg, 99%) of[2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol.The crystals were recrystallized from ethyl acetate-hexane. meltingpoint: 143-144° C.

Reference Example 88

To a mixture of[2-[-3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol(540 mg), triethylamine (0.350 mL) and ethyl acetate (50 mL) wasdropwise added methanesulfonyl chloride (0.145 mL) under ice-cooling andthe mixture was stirred at room temperature for 0.5 hr. To the reactionmixture was added water and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated to give an oil. To amixture of this oil and dimethyl sulfoxide (10 mL) was added a solutionof sodium cyanide (160 mg) in water (1 mL) at room temperature and themixture was stirred at room temperature for 2 hrs. To the reactionmixture was added water and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated. The obtained crystals wererecrystallized from ethyl acetate-hexane to give crystals (438 mg, 79%)of2-[2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile.melting point: 108-109° C.

Reference Example 89

To a mixture of[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanol (4.14 g),2-chloro-3-cyanopyridine (1.91 g) and N,N-dimethylformamide (50 mL) wasadded sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reactionmixture was stirred at room temperature for 3 hrs. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (4.65 g, 87%) of2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 135-136° C.

Reference Example 90

To a mixture of2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinonitrile(4.50 g) and anhydrous toluene (150 mL) was dropwise added a solution(0.95 M, 25.5 mL) of diisobutylaluminum hydride in hexane at −78° C. Thereaction mixture was allowed to warm to room temperature with stirringfor 1 hr. A saturated aqueous ammonium chloride solution (50 mL) wasdropwise added to the mixture and the mixture was further stirred atroom temperature for 15 min. To this mixture was added ethyl acetate andthe mixture was stirred at room temperature for 30 min., and theninsoluble materials were filtered off. The filtrate was washed withsaturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (2.60 g, 57%) of2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinaldehydefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 109-110° C.

Reference Example 91

To a mixture of2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinaldehyde(2.43 g), tetrahydrofuran (30 ml) and ethanol (30 mL) was added sodiumborohydride (0.23 g) at 0° C. and the mixture was stirred at roomtemperature for 30 min. Water was added to the reaction mixture, and theprecipitated solid was collected by filtration and dried with air togive crystals (2.34 g, 96%), of[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]-3-pyridyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 119-120° C.

Reference Example 92

To a mixture of[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]-3-pyridyl]methanol(2.12 g), triethylamine (1.09 g) and ethyl acetate (150 mL) was dropwiseadded methanesulfonyl chloride (1.24 g) under ice-cooling and themixture was stirred at room temperature for 3 hrs. The reaction mixturewas washed successively with water, saturated aqueous sodiumhydrogencarbonate and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated to give an oil. To a mixture of this oil anddimethyl sulfoxide (30 mL) was added an aqueous solution (3 mL) ofsodium cyanide (0.66 g) at room temperature and the mixture was stirredat room temperature for 3 hrs. To the reaction mixture was added waterand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (1.63 g, 75%) of2-[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:1, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 141-142° C.

Reference Example 93

To admixture of[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.50 g),2-chloro-3-cyanopyridine (1.91 g) and N,N-dimethylformamide (50 mL) wasadded sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reactionmixture was stirred at room temperature for 3 hrs. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (4.38 g, 77%) of2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinonitrilefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 120-121° C.

Reference Example 94

To a mixture of2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinonitrile(4.18 g) and anhydrous toluene (150 mL) was dropwise added a solution(0.95 M, 23.4 mL) of diisobutylaluminum hydride in hexane at −78° C. Thereaction mixture was allowed to warm to room temperature with stirringfor 1 hr. A saturated aqueous ammonium chloride solution (50 mL) wasdropwise added to the mixture and the mixture was further stirred atroom temperature for 15 min. Ethyl acetate was added to the mixture and,after stirring the mixture at room temperature for 30 min., insolublematerials were filtered off. The filtrate was washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was subjected to silica gel column chromatography togive crystals (2.35 g, 56%) of2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinaldehydefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 101-102° C.

Reference Example 95

To a mixture of2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinaldehyde(2.16 g), tetrahydrofuran (30 ml) and ethanol (30 mL) was added sodiumborohydride (0.20 g) at 0° C., and the mixture was stirred at roomtemperature for 30 min. Water was added to the reaction mixture, and theprecipitated solid was collected by filtration, and dried with air togive crystals (2.12 g, 97%) of[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 111-112° C.

Reference Example 96

To a mixture of[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]methanol(2.00 g), triethylamine (0.97 g) and ethyl acetate (150 mL) was dropwiseadded methanesulfonyl chloride (1.10 g) under ice-cooling and themixture was stirred at room temperature for 2 hrs. The reaction mixturewas washed successively with water, saturated aqueous sodiumhydrogencarbonate and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated to give an oil. To a mixture of this oil anddimethyl sulfoxide (30 mL) was added an aqueous solution (3 mL) ofsodium cyanide (0.59 g) at room temperature and the mixture was stirredat room temperature for 3 hrs. Water was added to the reaction mixture,and the precipitated crystals were collected by filtration. The obtainedcrystals were subjected to silica gel column chromatography to givecrystals (1.40 g, 68%) of2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from tetrahydrofuran-hexane gave colorless prismcrystals. melting point: 161-162° C.

Reference Example 97

A mixture of[4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]phenyl]methanol (0.90g), 5% palladium carbon (0.90 g) and tetrahydrofuran (100 mL) wassubjected to catalytic hydrogenation at room temperature and 1 atm.After filtering off the catalyst, the solvent was evaporated underreduced pressure to give crystals. (0.74 g, 81%) of[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 67-68° C.

Reference Example 98

To a mixture of diethyl malonate (115.8 g) and tetrahydrofuran (300 mL)was added sodium hydride (60%, oil, 24.12 g) under ice-cooling. Afterstirring the mixture at room temperature for 30 min., a solution (100mL) of 4-chloromethyl-5-methyl-2-phenyloxazole (50.0 g) intetrahydrofuran was added to the reaction mixture under ice-cooling, andthe mixture was heated under reflux for 1 hr. Water was added to thereaction mixture, and the mixture was concentrated. Ethyl acetate wasadded to the residue and the mixture was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated to give an oil.A mixture of this oil, 6N hydrochloric acid (300 mL) and acetic acid(150 ml) was heated under reflux for 20 hrs. The reaction mixture wasconcentrated, and ethyl acetate was added to the residue. The mixturewas washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated. The residue was subjected to silica gel columnchromatography to give crystals (22.4 g, 40%) of3-(5-methyl-2-phenyl-4-oxazolyl)propionic acid from a fraction elutedwith ethyl acetate-hexane (1:4, v/v). Recrystallization from ethylacetate-hexane gave colorless prism crystals. melting point: 124-125° C.

Reference Example 99

To a mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propionic acid (20.0 g),N,N-dimethylformamide (0.5 mL) and tetrahydrofuran; (300 mL) wasdropwise added oxalyl chloride (13.18 g) under ice-cooling, and themixture was stirred at room temperature for 1.5 hrs. The reactionmixture was concentrated, and the obtained residue was dissolved intetrahydrofuran (100 mL). This solution was dropwise added to a mixtureof 25% aqueous ammonia (200 mL) and tetrahydrofuran (100 mL) at roomtemperature. The reaction mixture was stirred at room temperature for1.5 hrs and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated to give crystals (15.4 g, 77%) of3-(5-methyl-2-phenyl-4-oxazolyl)propanamide. Recrystallization fromchloroform-ethanol gave colorless prism crystals. melting point:149-150° C.

Reference Example 100

A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide (10.0 g) and1,3-dichloro-2-propanone (5.35 g) was stirred at 130° C. for 2 hrs. Anaqueous potassium carbonate solution was added to alkalize the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The residue was subjected to silica gel columnchromatography to give crystals (2.30 g, 18%) of4-[2-(4-chloromethyl-2-oxazolyl)ethyl]-5-methyl-2-phenyloxazole from afraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:71-72° C.

Reference Example 101

A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide (10.44 g),2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide(14.64 g) and tetrahydrofuran (300 mL) was stirred at room temperaturefor 2 hrs. To the reaction mixture was added ethyl acetate, and themixture was washed successively with water and saturated brine, driedover anhydrous magnesium sulfate and concentrated. The obtained residuewas subjected to silica gel column chromatography to give crystals (10.7g, 96%) of 3-(5-methyl-2-phenyl-4-oxazolyl)propanethioamide from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:167-168° C.

Reference Example 102

A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanethioamide (5.47 g),1,3-dichloro-2-propanone (3.10 g) and ethanol (100 mL) was heated underreflux for 1 hr. The reaction mixture was concentrated, and ethylacetate was added to the residue. The organic layer was washedsuccessively with saturated aqueous sodium hydrogencarbonate andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (3.50 g, 49%) of4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:89-90° C.

Reference Example 103

To a mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide (5.0 g) andN,N-dimethylformamide (100 ml) was added phosphoryl chloride (3.33 g) atroom temperature and the mixture was stirred at room temperature for 1hr. To the reaction mixture was added water and the mixture wasextracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, dried over anhydrous magnesium sulfate,and concentrated to give crystals (4.10 g, 89%) of3-(5-methyl-2-phenyl-4-oxazolyl)propionitrile. Recrystallization fromethyl acetate-hexane gave colorless prism crystals. melting point:63-64° C.

A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propionitrile (8.20 g),hydroxylammonium chloride (4.02 g), potassium carbonate (4.01 g) and 70%ethanol (100 mL) was heated under reflux for 24 hrs. The reactionmixture was concentrated and water was added to the residue. Theobtained crystals were collected by filtration and washed with isopropylether. To a mixture of the obtained crystal, potassium carbonate (2.13g) and acetone (50 mL) was added chloroacetyl chloride (3.48 g) underice-cooling. The reaction mixture was stirred at room temperature for 15hrs. Water was added to the reaction mixture, and the precipitatedcrystals were collected by filtration and washed with isopropyl ether. Amixture of the obtained crystals and xylene (150 mL) was subjected toazeotropic dehydration for 4 hrs. The reaction mixture was concentrated,and ethyl acetate was added to the residue. The organic layer was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (2.56 g, 23%) of5-chloromethyl-3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazolefrom a fraction eluted with ethyl acetate-hexane (1:4, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 71-72° C.

Reference Example 104

To a mixture of[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (4.28 g),2-chloro-3-cyanopyridine (2.10 g) and N,N-dimethylformamide (5.0 mL) wasadded sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reactionmixture was stirred at 80° C. for 1 hr. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. The obtained residue was subjected to silicagel column chromatography to give crystals (1.90 g, 33%) of6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave pale-yellow prismcrystals. melting point: 116-117° C.

Reference Example 105

To a mixture of6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrile(1.70 g) and anhydrous toluene (80 mL) was dropwise added a solution(0.95 M, 9.5 mL) of diisobutylaluminum hydride in hexane at −78° C. Thereaction mixture was allowed to warm to room temperature with stirringfor 1 hr. A saturated aqueous ammonium chloride solution (30 mL) wasdropwise added to the mixture and the mixture was further stirred atroom temperature for 30 min. Ethyl acetate was added to the mixture and,after stirring the mixture at room temperature for 30 min., insolublematerials were filtered off. The filtrate was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theobtained residue was subjected to silica gel column chromatography togive crystals (0.98 g, 58%) of6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehydefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 114-115° C.

Reference Example 106

To a solution of methyl3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolecarboxylate (5.27 g)in tetrahydrofuran (100 ml) was slowly added diisobutylaluminum hydride(0.95 M hexane solution, 60 ml) at 0° C. and the mixture was stirred at0° C. for 1 hr. Sodium sulfate 10 hydrate (17.01 g) was added to thereaction mixture and the mixture was further stirred at room temperaturefor 30 min. The insoluble materials were removed by filtration, and thefiltrate was concentrated to give[3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolyl]methanol (3.88 g,80%) as colorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 84-85° C.

Reference Example 107

To a mixture of potassium t-butoxide (0.47 g) and dimethoxyethane (8 mL)was added a solution (8 mL) of toluenesulfonylmethylisocyanide (0.43 g)in dimethoxyethane at −78° C. Furthermore, a solution (8 mL) of6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehyde(0.84 g) in dimethoxyethane was added to the reaction mixture. Thereaction mixture was stirred at −78° C. for 1 hr. Methanol (10 mL) wasadded to the reaction mixture at room temperature and the mixture washeated under reflux for 30 min. To the reaction mixture was added waterand the mixture was extracted with ethyl acetate. The organic layer waswashed successively with saturated aqueous sodium hydrogencarbonate andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel, columnchromatography to give crystals (0.67 g, 79%) of2-[6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 122-123° C.

Reference Example 108

To a mixture of4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (3.23 g),tetrahydrofuran (15 ml) and methanol (15 ml) was added sodiumborohydride (0.378 g) at room temperature and the mixture was stirred atroom temperature for 30 min. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated to give crystals of4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol.Recrystallization from tetrahydrofuran-hexane gave pale-yellow platecrystals (3.22 g, 99%). melting point: 144-145° C.

Reference Example 109

A mixture of ethyl 3-methyl-1H-pyrazole-4-carboxylate (7.95 g),2-chloropyridine (5 ml), sodium hydride (0.60%, oil, 2.32 g) andN,N-dimethylformamide (150 ml) was stirred overnight at 180° C. Thereaction mixture was poured into water and extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated. The residue was subjectedto silica gel column chromatography to give ethyl3-methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylate (8.31 g, yield 73%) ascolorless crystals from a fraction eluted with ethyl acetate-hexane(1:9, volume ratio). The crystals were recrystallized from ethylacetate-hexane. melting point: 79-80° C.

Reference Example 110

To a solution of ethyl 3-methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylate(15.00 g) in tetrahydrofuran (150 mL) was added lithium aluminum hydride(1.93 g) at 0° C., and the mixture was stirred at room temperature for 1hr. Sodium sulfate 10 hydrate (21.03 g) and hexane (100 mL) were addedto the reaction mixture, and the mixture was stirred at room temperaturefor 1 hr. The precipitate was removed by filtration and the filtrate wasconcentrated. The obtained crystals were collected by filtration to give[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methanol (11.38 g). The crystalswere recrystallized from acetone-hexane. melting point: 116-117° C.

Reference Example 111

A mixture of 3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethanol (3.00 g),thionyl chloride (2.5 mL) and toluene (50 mL) was stirred at 70° C. for2 hrs. The reaction mixture was concentrated under reduced pressure, andsaturated aqueous sodium hydrogencarbonate was added to the residue. Themixture was extracted with ethyl acetate, and the ethyl acetate layerwas washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated to give4-chloromethyl-3-methyl-1-(2-pyridyl)-1H-pyrazole (3.10 g, yield 94%) asa colorless oil.

NMR (CDCl₃) δ: 2.44 (3H, s), 4.58 (2H, s), 7.46-7.60 (1H, m), 8.18-8.42(2H, m), 8.50-8.60 (1H, m), 9.43 (1H, s).

Reference Example 112

To a mixture of4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzaldehyde (3.50 g),methanol (5 mL) and tetrahydrofuran (25 mL) was added sodium borohydride(0.25 g) at 0° C. and the mixture was stirred at room temperature for 30min. The reaction mixture was concentrated under reduced pressure, anddilute hydrochloric acid was added to the residue. The mixture wasextracted with ethyl acetate and the ethyl acetate layer was washed withsaturated brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography to give4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-lymethoxy]benzyl alcohol (3.41 g,yield 97%) as colorless crystals from a fraction eluted with ethylacetate-hexane (1:2, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 83-84° C.

Reference Example 113

To a mixture of[3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolyl]methanol (1.80g), 2-chloro-3-cyanopyridine (0.83 g) and N,N-dimethylformamide (80 mL)was added sodium hydride (60%, oil, 0.26 g) under ice-cooling. Thereaction mixture was stirred at room temperature for 5 hrs. Water wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated. The obtained residue wassubjected to silica gel column chromatography to give crystals (2.08 g,86%) of2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 135-136° C.

Reference Example 114

To a mixture of2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile(1.90 g) and anhydrous toluene (100 mL) was dropwise added a solution(0.95 M, 16.3 mL) of diisobutylaluminum hydride in hexane at −78° C. Thereaction mixture was allowed to warm to room temperature with stirringfor 1.5 hrs. A saturated aqueous ammonium chloride solution (30 mL) wasdropwise added to the mixture and the mixture was further stirred atroom temperature for 30 min. Ethyl acetate was added to the mixture and,after stirring the mixture at room temperature for 30 min., an insolublematerials were filtered off. The filtrate was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theobtained residue was subjected to silica gel column chromatography togive crystals (0.80 g, 42%) of2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehydefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 123-124° C.

Reference Example 115

To a mixture of potassium t-butoxide (0.40 g) and dimethoxyethane (10mL) was added a solution (10 mL) of toluenesulfonylmethylisocyanide(0.37 g) in dimethoxyethane at −78° C. Further, a solution (10 mL) of2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehyde(0.70 g) in dimethoxyethane was added to the reaction mixture. Thereaction mixture was stirred at −78° C. for 1 hr. Methanol (10 mL) wasadded to the reaction mixture at room temperature and the mixture washeated under reflux for 30 min. To the reaction mixture was added waterand the mixture was extracted with ethyl acetate. The organic layer waswashed successively with saturated aqueous sodium hydrogencarbonate andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (0.45 g, 63%) of2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 103-104° C.

Reference Example 116

To a mixture of 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (5.64 g), methyl3-hydroxy-5-isoxazolecarboxylate (8.00 g), tributylphosphine (15.9 g)and tetrahydrofuran (200 mL) was added a solution (100 mL) of1,1′-(azodicarbonyl)dipiperidine (19.9 g) in tetrahydrofuran at roomtemperature and the mixture was stirred for 15 hrs. The precipitatedcrystals were removed by filtration and the filtrate was concentrated.The residue was subjected to silica gel column chromatography to givecrystals (9.50 g, 73%) of methyl3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-isoxazolecarboxylate from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:90-91° C.

Reference Example 117

To a mixture of methyl3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-isoxazolecarboxylate (9.2g) and tetrahydrofuran (200 mL) was added lithium aluminum hydride (1.06g) under ice-cooling, and the mixture was stirred at room temperaturefor 30 min. Dilute hydrochloric acid was added to acidify the mixtureand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (4.90 g, 58%) of[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-isoxazolyl]methanol from afraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:115-116° C.

Reference Example 118

To a mixture of 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (9.90 g), methyl6-chloronicotinate (8.36 g) and N,N-dimethylformamide (100 mL) was addedsodium hydride (60%, oil, 2.40 g) under ice-cooling. The reactionmixture was stirred at room temperature for 3 hrs. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give a mixture of methyl6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]nicotinate and[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]nicotinate from a fractioneluted with ethyl acetate-hexane (1:4, v/v). To a mixture of theobtained mixture (8.41 g) and tetrahydrofuran (200 mL) was added lithiumaluminum hydride (1.85 g) under ice-cooling, and the mixture was stirredat room temperature for 1 hr. Sodium sulfate 10 hydrate (15.7 g) wasadded to the mixture and hexane and ethyl acetate were added, and themixture was stirred at room temperature for 30 min. The insolublematerials were removed by filtration, and the filtrate was concentrated.The obtained residue was subjected to silica gel column chromatographyto give crystals (4.08 g, 27%) of[6-[2-[(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridyl]methanol from afraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:112-113° C.

Reference Example 119

A mixture of 2-methyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine(18.04 g), 3-chloroperbenzoic acid (18.85 g) and tetrahydrofuran (100mL) was stirred overnight at room temperature and concentrated. Theresidue was subjected to silica gel column chromatography to give acolorless oil from a fraction eluted with tetrahydrofuran. A solution ofthe obtained colorless oil in acetic anhydride (100 mL) was slowly addedto acetic anhydride (200 mL) heated to 130° C. and the mixture wasstirred for 2 hrs. and concentrated. The residue was dissolved in ethylacetate, washed with saturated aqueous sodium hydrogencarbonate and thenwith saturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography to give[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl] acetate (18.09g, yield 83%) as a colorless oil from a fraction eluted with ethylacetate-hexane (1:2, volume ratio).

NMR (CDCl₃) δ: 2.13 (3H, s), 2.45 (3H, s), 5.05 (2H, s), 5.16 (2H, s),7.26-7.50 (5H, m), 7.94-8.05 (2H, m), 8.38-8.43 (1H, m).

Reference Example 120

A mixture of[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]acetate (18.0g), 1N aqueous sodium hydroxide solution (75 mL) and methanol (100 mL)was stirred at room temperature for 3 hrs. and concentrated. The residuewas dissolved in ethyl acetate, washed with water and then withsaturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained colorless crystals were collected byfiltration to give5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethanol (14.29 g,yield 91%). The crystals were recrystallized from ethyl acetate-hexane.melting point: 125-126° C.

Reference Example 121

To a mixture of (5-methyl-2-phenyl-4-thiazolyl)methanol (5.0 g),6-chloro-3-cyanopyridine (3.38 g) and N,N-dimethylformamide (100 mL) wasadded sodium hydride (60%, oil, 1.07 g) under ice-cooling. The reactionmixture was stirred at room temperature for 1 hr. Water was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was subjectedto silica gel column chromatography to give crystals (5.55 g, 74%) of6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinonitrile from afraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:124-125° C.

Reference Example 122

To a mixture of6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinonitrile (5.45 g) andanhydrous toluene (150 mL) was dropwise added a solution (0.95 M, 41.0mL) of diisobutylaluminum hydride in hexane at −78° C. The reactionmixture was allowed to warm to room temperature with stirring for 1.5hrs. A saturated aqueous ammonium chloride solution (100 mL) wasdropwise added to the mixture, and the mixture was further stirred atroom temperature for 30 min. Ethyl acetate was added to the mixture andthe mixture was stirred at room temperature for 30 min. Insolublematerials were filtered away. The filtrate was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated. Theobtained residue was subjected to silica gel column chromatography togive crystals (4.30 g, 78%) of6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinaldehyde from afraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:120-121° C.

Reference Example 123

To a mixture of6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinaldehyde (4.20 g),tetrahydrofuran (50 ml) and ethanol (50 mL) was added sodium borohydride(0.51 g) at room temperature and the mixture was stirred at roomtemperature for 30 min. To the reaction mixture was added water and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated to give crystals (4.10 g, 97%) of[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 70-71° C.

Reference Example 124

To a mixture of [2-(2-furyl)-5-methyl-4-oxazolyl]methanol (5.18 g),6-chloro-3-cyanopyridine (4.00 g) and N,N-dimethylformamide (100 mL) wasadded sodium hydride (60%, oil, 1.27 g) under ice-cooling. The reactionmixture was stirred at room temperature for 1 hr. Water was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theorganic layer was washed successively with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated. The obtainedresidue was subjected to silica gel column chromatography to givecrystals (6.97 g, 86%) of6-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]nicotinonitrile from afraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallizationfrom ethyl acetate-hexane gave colorless prism crystals. melting point:105-106° C.

Reference Example 125

To a mixture of6-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]nicotinonitrile (6.77 g) andanhydrous toluene (150 mL) was dropwise added a solution (0.95 M, 55.8mL) of diisobutylaluminum hydride in hexane at −78° C. The reactionmixture was allowed to warm to room temperature with stirring for 1 hr.A saturated aqueous ammonium chloride solution (100 mL) was dropwiseadded to the mixture and the mixture was further stirred at roomtemperature for 30 min. Ethyl acetate was added to the mixture and themixture was stirred at room temperature for 30 min. Insoluble materialswere filtered off. The filtrate was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated. The obtained residuewas subjected to silica gel column chromatography to give crystals (3.25g, 47%) of 6-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]nicotinaldehydefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 139-140° C.

Reference Example 126

To a mixture of6-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]nicotinaldehyde (3.10 g),tetrahydrofuran (50 ml) and ethanol (50 mL) was added sodium borohydride(0.41 g) at room temperature and the mixture was stirred at roomtemperature for 30 min. To the reaction mixture was added water and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated to give crystals (2.86 g, 92%) of[6-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-pyridyl]methanol.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 120-121° C.

Reference Example 127

A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (20.18 g),4-benzyloxyphenol (17.70 g), anhydrous potassium carbonate (12.22 g) andN,N-dimethylformamide (200 mL) was stirred at 90° C. for 15 hrs. Thereaction mixture was poured into water, and the precipitated solid wascollected by filtration, and dried with air to give crystals (29.03 g,88%) of 4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole.Recrystallization from ethyl acetate-hexane gave colorless leafletcrystals. melting point: 126-127° C. A mixture of the obtained4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole (22.6 g), 5%palladium carbon (10.0 g) and tetrahydrofuran (300 mL) was subjected tocatalytic hydrogenation at room temperature and 1 atm. After filteringoff the catalyst, the solvent was evaporated under reduced pressure togive crystals (16.3 g, 95%) of4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenol. Recrystallization fromethyl acetate-hexane gave colorless prism crystals. melting point:168-169° C.

Reference Example 128

To a mixture of benzyl alcohol (32.0 g), 2-chloro-3-cyanopyridine (37.3g) and N,N-dimethylformamide (200 mL) was added sodium hydride (60%,oil, 12.92 g) under ice-cooling. The reaction mixture was stirred atroom temperature for 3 days. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The organic layer waswashed successively with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated. The obtained residue was subjectedto silica gel column chromatography to give 2-(benzyloxy)nicotinonitrileas an oil (39.13 g, 69%) from a fraction eluted with ethylacetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 5.52 (2H, s), 6.99 (1H, dd, J=7.6, 5.2 Hz), 7.31-7.52(5H, m), 7.89 (1H, dd, J=7.6, 2.0 Hz), 8.36 (1H, dd, J=5.2, 2.0 Hz).

To a mixture of 2-(benzyloxy)nicotinonitrile (47.50 g) and anhydroustoluene (100 mL) was dropwise added a solution (1 M, 500 mL) ofdiisobutylaluminum hydride in hexane at −78° C. The reaction mixture wasallowed to warm to room temperature with stirring for 1.5 hrs. Asaturated aqueous ammonium chloride solution was dropwise added to themixture and the mixture was stirred at room temperature for 30 min.Ethyl acetate was added to the mixture, and the mixture was furtherstirred at room temperature for 30 min. Insoluble materials werefiltered off. The filtrate was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue wassubjected to silica gel column chromatography to give2-(benzyloxy)nicotinaldehyde as an oil (19.71 g, 41%) from a fractioneluted with ethyl acetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 5.54 (2H, s), 7.04 (1H, dd, J=7.4, 5.2 Hz), 7.26-7.50(5H, m), 8.14 (1H, dd, J=7.4-2.0 Hz), 8.40 (1H, dd, J=5.2, 2.0 Hz),10.45 (1H, s).

To a mixture of potassium t-butoxide (4.52 g) and dimethoxyethane (20mL) was added a solution (20 mL) of toluenesulfonylmethylisocyanide(4.12 g) in dimethoxyethane at −78° C. Further, a solution (20 mL) of2-(benzyloxy)nicotinaldehyde (4.12 g) in dimethoxyethane was added tothe reaction mixture. The reaction mixture was stirred at −78° C. for 1hr. Methanol (20 mL) was added to the reaction mixture at roomtemperature and the mixture was heated under reflux for 30 min. To thereaction mixture was added water and the mixture was extracted withethyl acetate. The organic layer was washed successively with saturatedaqueous sodium hydrogencarbonate and saturated brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue wassubjected to silica gel column chromatography to give2-(2-benzyloxy-3-pyridyl)acetonitrile as an oil from a fraction elutedwith ethyl acetate-hexane (1:8, v/v).

¹H-NMR (CDCl₃) δ: 3.70 (2H, s), 5.44 (2H, s), 6.95 (1H, dd, J=7.4, 5.0Hz), 7.32-7.49 (5H, m), 7.71 (1H, dd, J=7.4, 1.8 Hz), 8.17 (1H, dd,J=5.0, 1.8 Hz).

A mixture of 2-(2-benzyloxy-3-pyridyl)acetonitrile (1.0 g) and 10%hydrogen chloride-methanol (30 mL) was stirred at room temperature for 3days. The reaction mixture was concentrated, and saturated aqueoussodium hydrogencarbonate was added to basify the residue. The mixturewas concentrated and a mixed solvent of ethyl acetate andtetrahydrofuran (3:1, v/v) was added to the residue. Insoluble materialswere removed by filtration. The filtrate was dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.42 g, 56%) ofmethyl 2-(2-oxo-1,2-dihydro-3-pyridyl)acetate. Recrystallization fromethyl acetate-hexane gave colorless prism crystals. melting point:183-184° C.

Reference Example 129

To a mixture of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenol (2.70g), ethyl 2-chloromethylnicotinate (1.74 g) and N,N-dimethylformamide(100 mL) was added sodium hydride (60%, oil, 0.42 g) under ice-cooling.The reaction mixture was stirred at room temperature for 2 hrs. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed successively with water and saturatedbrine, dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was subjected to silica gel column chromatography togive ethyl2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]nicotinateas a colorless oil (2.45 g, 63%) from a fraction eluted with ethylacetate-hexane (1:4, v/v).

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 2.41 (3H, s), 4.34 (2H, q,J=7.2 Hz), 4.93 (2H, s), 5.48 (2H, s), 6.91-6.93 (4H, m), 7.32-7.45 (4H,m), 7.97-8.04 (2H, m), 8.19-8.24 (1H, m), 8.72-8.76 (1H, m).

Reference Example 130

To a mixture of ethyl2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]nicotinate(2.4 g), sodium borohydride (1.02 g) and tetrahydrofuran (100 ml) wasdropwise added methanol (10 mL) at 60° C. The reaction mixture wasstirred at 60° C. for 1 hr. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The organic layer waswashed successively with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]methanolas a colorless oil (2.15 g, 99%).

¹H-NMR (CDCl₃) δ: 2.41 (3H, s), 2.63 (1H, brs), 4.80-4.82 (2H, m), 4.93(2H, s), 5.25 (2H, s), 6.92-6.95 (4H, m), 7.29 (1H, dd, J=7.8, 4.8 Hz),7.39-7.47 (3H, m), 7.82 (1H, dd, J=7.8, 1.8 Hz), 7.97-8.04 (2H, m), 8.53(1H, dd, J=4.8, 1.8 Hz).

Reference Example 131

To a mixture of[2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]methanol(2.10 g), triethylamine (1.05 g) and ethyl acetate (100 mL) was dropwiseadded methanesulfonyl chloride (1.19 g) under ice-cooling, and themixture was stirred at room temperature for 2.5 hrs. The reactionmixture was washed successively with water, saturated aqueous sodiumhydrogencarbonate and saturated brine, dried over anhydrous magnesiumsulfate and concentrated to give an oil. To a mixture of this oil anddimethyl sulfoxide (50 mL) was added an aqueous solution (5 mL) ofsodium cyanide (0.51 g) at room temperature and the mixture was stirredat room temperature for 2 hrs. To the reaction mixture was added waterand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (1.49 g, 70%) of2-[2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:1, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 134-135° C.

Reference Example 132

To a mixture of[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]phenyl]methanol(2.00 g), 2-chloro-3-cyanopyridine (1.00 g) and N,N-dimethylformamide(20 mL) was added sodium hydride (60%, oil, 0.30 g) under ice-cooling.The reaction mixture was stirred at room temperature for 3 hrs. Waterwas added to the reaction mixture and the mixture was extracted withethyl acetate. The organic layer was washed successively with water andsaturated brine dried over anhydrous magnesium sulfate and concentratedto give crystals (2.48 g, 92%) of2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinonitrile.Recrystallization from acetone-hexane gave colorless prism crystals.melting point: 108-109° C.

Reference Example 133

To a mixture of2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinonitrile(2.03 g) and anhydrous toluene (100 mL) was dropwise added a solution(0.95 M, 11.8 mL) of diisobutylaluminum hydride in hexane at −78° C. Thereaction mixture was allowed to warm to room temperature with stirringfor 1 hr. A saturated aqueous ammonium chloride solution (30 mL) wasdropwise added to the mixture and the mixture was further stirred atroom temperature for 30 min. Ethyl acetate was added to the mixture andthe mixture was stirred at room temperature for 30 min. Insolublematerials were filtered off, and the filtrate was washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was subjected to silica gel column chromatography togive crystals (0.61 g, 30%) of2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinaldehydefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 106-1-07° C.

Reference Example 134

To a mixture of potassium t-butoxide (0.30 g) and dimethoxyethane (10mL) was added a solution (10 mL) of toluenesulfonylmethylisocyanide(0.27 g) in dimethoxyethane at −78° C. Further, a solution (10 mL) of2-[4-[[3-methyl-1-(2-yridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinaldehyde(0.52 g) in dimethoxyethane was added to the reaction mixture. Thereaction mixture was stirred at −78° C. for 1 hr. Methanol (10 mL) wasadded to the reaction mixture at room temperature and the mixture washeated under reflux for 30 min. To the reaction mixture was added waterand the mixture was extracted with ethyl acetate. The organic layer waswashed successively with saturated aqueous sodium hydrogencarbonate andsaturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (0.38 g, 72%) of2-[2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 138-139° C.

Reference Example 135

To a solution of 2-methylamino-4-phenylthiazole (1.76 g) inN,N-dimethylformamide (25 mL) was gradually added sodium hydride (60%,oil, 351 mg) at room temperature and the mixture was stirred for 30 min.Methyl 4-bromobenzoate (2.11 g) was added, and the mixture was furtherstirred for 1.5 hrs. To the reaction mixture was added water and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography to give methyl4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzoate (2.56 g, 86%) as ayellow oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v).

¹H-NMR (CDCl₃) δ: 3.08 (3H, s), 3.90 (3H, s), 4.85 (2H, s), 6.75 (1H,s), 7.27-7.43 (5H, m), 7.86 (2H, dd, J=8.4, 1.4 Hz), 8.02 (1H, d, J=8.4Hz).

Reference Example 136

To a solution of methyl4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzoate (2.06 g) intetrahydrofuran (30 mL) was dropwise added a solution (0.9 M, 30 mL) ofdiisobutylaluminum hydride in hexane at 0° C. and the mixture wasstirred at room temperature for 2 hrs. Diethyl ether was added to thereaction mixture, sodium sulfate 10 hydrate was further added and themixture was stirred for 2 hrs. After filtering off insoluble materials,the filtrate was concentrated. The residue was subjected to silica gelcolumn chromatography to give white crystals (1.85 g, 98%) of4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyl alcohol from afraction eluted with ethyl acetate-hexane (1:1, v/v). melting point:88-90° C.

Reference Example 137

To a mixture of[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolyl]methanol (2.00 g),2-chloro-3-cyanopyridine (1.16 g) and N,N-dimethylformamide (60 mL) wasgradually added sodium hydride (60%, oil, 335 mg) under ice-cooling.After stirring the reaction mixture at room temperature for 90 min.,water was added to the reaction mixture. The mixture was neutralizedwith 2N hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with water, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (2.61 g, 96%) of2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrilefrom a fraction eluted with ethyl acetate-hexane (1:1, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 139-140° C.

Reference Example 138

To a mixture of2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile(2.60 g) and anhydrous toluene (100 mL) was dropwise added a solution(0.95 M, 15.5 mL) of diisobutylaluminum hydride in hexane at −78° C. Thereaction mixture was allowed to warm to room temperature with stirringfor 1.5 hrs. A saturated aqueous ammonium chloride solution (30 mL) wasdropwise added to the mixture and the mixture was further stirred atroom temperature for 30 min. Ethyl acetate was added to the mixture andthe mixture was washed with saturated aqueous ammonium chloride solutionand then with saturated brine. The organic layer was dried overanhydrous magnesium sulfate and concentrated. The obtained residue wassubjected to silica gel column chromatography to give crystals (1.70 g,65%) of2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehydefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless needlecrystals. melting point: 90-91° C.

Reference Example 139

To a mixture of2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehyde(1.64 g), tetrahydrofuran (20 ml) and ethanol (20 mL) was added sodiumborohydride (80 mg) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. Water was added to the reaction mixture, and theprecipitated crystals were collected by filtration and recrystallizedfrom ethyl acetate-isopropyl ether to give colorless needle crystals(1.50 g, 91%) of[2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]methanol.melting point: 136-137° C.

Reference Example 140

To a mixture of[2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]methanol(1.47 g), triethylamine (760 mg) and ethyl acetate (150 mL) was dropwiseadded methanesulfonyl chloride (860 mg) under ice-cooling and themixture was stirred at room temperature or 2 hrs. The reaction mixturewas washed with water, dried over anhydrous magnesium sulfate andconcentrated to give an oil. To a mixture of this oil and dimethylsulfoxide (50 mL) was added an aqueous solution (5 mL) of sodium cyanide(280 mg) at room temperature and the mixture was stirred at roomtemperature for 12 hrs. To the reaction mixture was added water and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with water, dried over anhydrous magnesium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography to give crystals (1.40 g, 68%) of2-[2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals (1.07 g, 71%). melting point: 110-111° C.

Reference Example 141

To a mixture of4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzaldehyde (6.00 g),tetrahydrofuran (80 mL) and methanol (20 mL) was gradually added sodiumborohydride (330 mg) at room temperature. After stirring for 30 min.,water was added to the reaction mixture, and the precipitated crystalswere collected by filtration and recrystallized from acetone-methanol togive colorless prism crystals (5.76 g, 95%) of4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyl alcohol. meltingpoint: 181-182° C.

Reference Example 142

To a mixture of 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzylalcohol (4.00 g), 2-chloro-3-cyanopyridine (2.41 g) andN,N-dimethylformamide (80 mL) was gradually added sodium hydride (60%,oil, 700 mg) under ice-cooling. After stirring the reaction mixture atroom temperature for 2 hrs, water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with water, dried over anhydrous magnesium sulfate andconcentrated. Recrystallization from ethyl acetate-isopropyl ether gavecolorless prism crystals (4.02 g, 78%) of2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]nicotinonitrile.melting point: 145-146° C.

Reference Example 143

To a mixture of2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]nicotinonitrile(2.30 g) and toluene (50 mL) was dropwise added a solution (0.95 M, 16.2mL) of diisobutylaluminum hydride in hexane at −78° C. The mixture wasstirred at room temperature for 1 hr. A saturated aqueous ammoniumchloride solution (30 mL) was dropwise added to the mixture and themixture was further stirred at room temperature for 30 min. Ethylacetate was added to the mixture, and the mixture was washed withsaturated aqueous ammonium chloride solution and then with saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andconcentrated to give crystals (1.50 g, 65%) of the correspondingaldehyde. To a mixture of this crystal (1.50 g), tetrahydrofuran (30 mL)and ethanol (30 mL) was gradually added sodium borohydride (80 mg) atroom temperature. After stirring for 1 hr., water was added to thereaction mixture, and the precipitated crystals were collected byfiltration. Recrystallization from acetone-hexane gave colorless prismcrystals (1.30 g, 86%) of[2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]-3-pyridyl]methanol.melting point: 161-162° C.

Reference Example 144

To a mixture of [2-[4-[5-methyl-2-7(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]-3-pyridyl]methanol (1.25 g),triethylamine (570 mg) and tetrahydrofuran (80 mL) was dropwise addedmethanesulfonyl chloride (650 mg) under ice-cooling and the mixture wasstirred at room temperature for 3 hrs. The reaction mixture was pouredinto water, and the precipitated crystals were collected by filtrationand washed with water and then isopropyl ether. The crystals weredissolved in dimethyl sulfoxide (25 mL) and a solution of sodium cyanide(200 mg) in water (3 mL) was added at room temperature. The mixture wasstirred at room temperature for 2 hrs. To the reaction mixture was addedwater and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with water, dried over anhydrous magnesiumsulfate and concentrated. The residue was subjected to silica gel columnchromatography to give crystals of2-[2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]-3-pyridyl]acetonitrilefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals (770 mg, 60%). melting point: 182-183° C.

Reference Example 145

A mixture of 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (3.22 g), thionyl chloride (0.73 ml) and toluene (50 ml) wasrefluxed for 1 hr. The reaction mixture was concentrated and saturatedaqueous sodium hydrogencarbonate was added. The mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was subjected to silica gel column chromatography to give4-(5-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (2.59g, yield 75%) as colorless crystals from a fraction eluted with ethylacetate. The crystals were recrystallized from ethyl acetate-hexane.melting point: 129-130° C.

Reference Example 146

To a mixture of[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxyphenyl]methanol(5.00 g), 2-chloro-3-cyanopyridine (2.65 g) and N,N-dimethylformamide(150 mL) was added sodium hydride (60%, oil, 0.70 g) at room temperatureand the mixture was stirred for 15 hrs. Water was added to the reactionmixture and the precipitated crystals were collected by filtration togive crystals (6.60 g, yield 99%) of3-cyano-2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]pyridine.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 137-138° C.

Reference Example 147

To a mixture of3-cyano-2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]pyridine(6.30 g) and anhydrous toluene (250 mL) was dropwise added a solution(0.95 M, 47 mL) of diisobutylaluminum hydride in hexane at −78° C. Thereaction mixture was allowed to warm to room temperature with stirringfor 1 hr. A saturated aqueous ammonium chloride solution (50 mL) wasdropwise added to the reaction mixture at 0° C. and ethyl acetate wasfurther added. Insoluble materials were filtered off and the filtratewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography to give crystals (1.0 g, yield 16%) of2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]-3-pyridinecarbaldehydefrom a fraction eluted with ethyl acetate-hexane (2:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 120-121° C.

Reference Example 148

To a mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(3.00 g), 3-mercaptobenzoic acid (1.47 g) and N,N-dimethylformamide (30mL) was dropwise added triethylamine (2.13 g) at room temperature. Thereaction mixture was stirred at room temperature for 1 hr. The reactionmixture was poured into water, acidified with 2N hydrochloric acid, andextracted with ethyl acetate. The organic layer was washed with water,dried over anhydrous magnesium sulfate and concentrated. The residue wassubjected to silica gel column chromatography to give crystals (3.70 g,yield 90%) of3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzoic acid froma fraction eluted with acetone-hexane (1:1, v/v). Recrystallization fromethyl acetate gave colorless prism crystals. melting point: 129-130° C.

Reference Example 149

A mixture of3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzoic acid(3.20 g), conc. sulfuric acid (1 mL) and methanol (50 mL) was stirredwith heating under reflux for 1 hr. The reaction mixture wasconcentrated, water was added to the residue and the mixture wasextracted with ethyl acetate. The organic layer was washed with water,dried over anhydrous magnesium sulfate and concentrated. The residue wassubjected to silica gel column chromatography to give methyl3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzoate as anoil (2.20 g, yield 67%) from a fraction eluted with ethyl acetate-hexane(1:4, v/v).

¹H-NMR (CDCl₃) δ: 2.42 (3H, s), 3.91 (3H, s), 4.14 (2H, s), 4.96 (2H,s), 6.90-7.01 (3H, m), 7.17-7.34 (2H, m), 7.43-7.46 (4H, m), 7.81-7.85(1H, m), 7.99-8.04 (3H, m).

Reference Example 150

To a mixture of methyl3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzoate (2.20 g)and tetrahydrofuran (80 mL) was added lithium aluminum hydride (0.19 g)under ice-cooling, and the mixture was stirred for 2 hrs. The reactionmixture was poured into iced water, acidified with 2N hydrochloric acidand extracted with ethyl acetate. The organic layer was washed withwater, dried over anhydrous magnesium sulfate and concentrated. Theobtained oil was dissolved in toluene (80 mL). Manganese dioxide (6.0 g)was added to the mixture and the mixture was stirred at room temperaturefor 2 hrs. The reaction mixture was filtrated and the filtrate wasconcentrated. The residue was subjected to silica gel columnchromatography to give3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzaldehyde asan oil (1.55 g, yield 76%) from a fraction eluted with ethylacetate-hexane (1:3, v/v).

¹H-NMR (CDCl₃) δ: 2.42 (3H, m), 4.16 (2H, s), 4.96 (2H, s), 6.89-6.93(2H, m), 7.00-7.02 (1H, m), 7.18-7.22 (1H, m), 7.35-7.53 (5H, m),7.63-7.68 (1H, m), 7.77-7.79 (1H, m), 7.99-8.04 (2H, m), 9.93 (1H, s).

Reference Example 151

A mixture of3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzaldehyde(0.80 g), diethyl malonate (0.37 g), benzoic acid (0.07 g), piperidine(0.05 g) and toluene (40 mL) was heated under reflux for 4 hrs. withazeotropic dehydration. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The organic layer was washed successively with saturated aqueous sodiumhydrogencarbonate, dilute hydrochloric acid and water, dried overanhydrous magnesium sulfate and concentrated. The residue was subjectedto silica gel column chromatography to give an oil from a fractioneluted with acetone-hexane (1:5, v/v). To a mixture of the obtained oil,tetrahydrofuran (20 mL) and ethanol (20 mL) was added sodium borohydride(0.02 g) at 0° C. and the mixture was stirred at 0° C. for 1 hr. Thereaction mixture was poured into water, acidified with 2N hydrochloricacid and extracted with ethyl acetate. The organic layer was washed withwater, dried over anhydrous magnesium sulfate and concentrated. Theresidue was subjected to silica gel column chromatography to givediethyl2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzyl]malonateas an oil (0.71 g, yield 66%) from a fraction eluted with ethylacetate-hexane (1:4, v/v).

¹H-NMR (CDCl₃) δ: 1.20 (6H, t, J=7.2 Hz), 2.43 (3H, s), 3.16 (2H, d,J=7.8 Hz), 3.59 (1H, t, J=7.8 Hz), 4.08 (2H, s), 4.15 (4H, q, J=7.2 Hz),4.96 (2H, s), 6.87-6.92 (2H, m), 6.99-7.04 (2H, m), 7.14-7.25 (4H, m),7.42-7.45 (3H, m), 7.99-8.05 (2H, m).

Reference Example 152

To a mixture of potassium t-butoxide (0.38 g) and dimethoxyethane (10mL) was added a solution of toluenesulfonylmethylisocyanide (0.33 g) indimethoxyethane (5 mL) at −78° C. and the mixture was stirred for 10min. A solution (10 mL) of3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzaldehyde(0.70 g) in dimethoxyethane was added to the reaction mixture and themixture was stirred for 30 min at −78° C. Methanol (25 mL) was added tothe reaction mixture at room temperature and the mixture was heatedunder reflux for 1 hr. The reaction mixture was concentrated, water wasadded to the residue, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated. The residue was subjected to silicagel column chromatography to give2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetonitrileas an oil (0.295 g, yield 41%) from a fraction eluted withacetone-hexane (1:5, v/v).

¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 3.68 (2H, s), 4.11 (2H, s), 4.96 (2H,s), 6.89-7.00 (3H, m), 7.18-7.26 (5H, m), 7.42-7.46 (3H, m), 7.99-8.04(2H, m).

Reference Example 153

(4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]phenyl)methanol (400 g) andthen 2-chloro-3-cyanopyridine (206.7 g) were added to dimethylformamide(1.6 L). To the obtained mixture was added triturated sodium hydroxide(59.4 g) and the mixture was stirred at 20-30° C. for 48 hrs. Water (1.6L) was dropwise added at the same temperature and the mixture wasstirred for 2 hrs. The precipitated crystals were collected byfiltration, washed with water (1.6 L) and then ice-cooled ethyl acetate(800 ml), and dried (40° C.) under reduced pressure to give2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)nicotinonitrileas white crystals.

¹H-NMR (DMSO-d₆, δ, 300 MHz); 2.42 (3H, s), 4.99 (2H, s), 5.45 (2H, s),6.93-7.03 (3H, m), 7.41-7.44 (5H, m), 7.84-=7.88 (1H, m), 7.98-8.02 (2H,m), 8.33-8.36 (1H, m).

Reference Example 154

2-({4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)nicotinonitrile(5.42 g) was added to toluene (189.6 ml) under an argon stream andcooled to −65° C. To the obtained mixture was dropwise added a 1.5 Msolution (20 m) of diisobutylaluminum hydride in toluene and the mixturewas stirred at the same temperature for 30 min. and raised to −20° C. Asaturated Rochelle salt solution (100 ml) was dropwise added to theobtained mixture and water (50 ml) was further added. After stirring at40° C. for 10 min., the mixture was partitioned. The aqueous layer wasextracted with toluene (20 ml). The organic layers were combined, washedwith water and concentrated under reduced pressure. The residue wasdissolved in toluene/ethyl acetate=20/1 (50 ml) and silica gel (10.8 g)was added to the mixture. The mixture was stirred for 1 hr. Silica gelwas filtrated and washed with toluene/ethyl acetate=20/1 (58 ml). Thefiltrates were combined and, after concentration under reduced pressure,the residue was dissolved in tetrahydrofuran (31 ml). A solution ofsodium hydrogensulfite (1.193 g) in water (3 ml) was added to theobtained solution and the mixture was stirred at room temperature for 3hrs. The crystallized crystals were collected by filtration washed withice-cooled tetrahydrofuran and dried under reduced pressure to givesodiumhydroxy[2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)pyridin-3-yl]methanesulfonateas white crystals.

¹H-NMR (DMSO-d₆, δ, 300 MHz); 2.44 (3H, s), 4.99 (2H, s), 5.25 (2H, s),5.32 (1H, d, J=6.1 Hz), 5.75 (1H, d, J=6.1 Hz), 6.90-6.94 (1H, m), 7.02(2H, d, J=8.6 Hz), 7.43 (2H, d, J=8.6 Hz), 7.49-7.52 (3H, m), 7.90-8.02(4H, m).

Reference Example 155

Under an argon stream,2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)nicotinonitrile(5.42 g) was added to toluene (189.6 ml). The obtained mixture wascooled to −65° C., and a 1.5 M solution (20 ml) of diisobutylaluminumhydride in toluene was dropwise added. The mixture was stirred at thesame temperature for 1 hr and 45 min. A saturated ammonium chloridesolution (54 ml) was dropwise added to the reaction solution and themixture was stirred at room temperature. Insoluble materials werefiltered off, the solution was washed with ethyl acetate (27 ml) andpartitioned. The organic layer was washed with 10% Rochelle saltsolution and water and concentrated under reduced pressure. The residuewas dissolved in toluene/ethyl acetate=5/1 (54 ml) and silica gel (16 g)was added. The mixture was stirred for 1 hr. Silica gel was filtratedoff, and washed with toluene/ethyl acetate=5/1 (54 ml). The filtrateswere combined and concentrated under reduced pressure. The residue wasdissolved in tetrahydrofuran (32 ml) and a solution of sodiumhydrogensulfite (1.9 g) in water (3.2 ml) was added to the mixture, andthe mixture was stirred at room temperature for 45 min. A solution ofsodium hydrogensulfite (630 mg) in water (1 ml) was added to thereaction solution and the mixture was stirred at room temperature for 13hrs. To the reaction solution was added isopropyl ether (6.4 ml) and themixture was stirred at room temperature for 30 min. and underice-cooling for 1 hr. The crystallized crystals were filtrated off andwashed with ice-cooled tetrahydrofuran/isopropyl ether=1/1 (12 ml) togive sodiumhydroxy[2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)pyridin-3-yl]methanesulfonate.

This compound was added to a mixture of ethyl acetate (54 ml) and 10%sodium carbonate (54 ml) and the mixture was stirred for 30 min. andpartitioned. The organic layer was washed with 10% brine (54 ml), andthen with 5% brine (54 ml) and concentrated under reduced pressure. Tothe residue was added ethyl acetate (5.4 ml) and the residue wasdissolved under reflux. The obtained solution was stirred for 1 hr. andn-hexane (16.2 ml) was added to the solution. The mixture was stirred atroom temperature for 1 hr, and then under ice-cooling for 1 hr. Theprecipitated crystals were filtrated off and washed with ice-cooledethyl acetate/n-hexane=1/1 (35 ml) and dried under reduced pressure at40° C. to give2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)nicotinaldehydeas white crystals.

¹H-NMR (CDCl₃, δ, 300 MHz); 2.43 (3H, s), 5.01 (2H, s), 5.47 (2H, s),7.01-7.06 (3H, m), 7.41-7.45 (5H, m), 7.99-8.03 (2H, m), 8.10-8.13 (1H,m), 8.37-8.40 (1H, m), 10.40 (1H, s).

Reference Example 156

Distilled water (150 ml) was added to Raney-nickel (75 ml), and afterstirring, the supernatant was decanted. This step was repeated 3 timesand distilled water (50 ml) and pyridine (250 ml) were added toRaney-nickel under a nitrogen stream. The obtained mixture was heated to40° C. and a solution of sodium phosphinate monohydrate (260 g) indistilled water (200 ml) was dropwise added at 40-60° C. over 30 min.The mixture was stirred at 50-60° C. for 15 min. Formic acid (250 ml)was dropwise added to the reaction solution at 50-60° C. over 30 min anda solution of2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)nicotinonitrile(50 g) in pyridine (250 ml) was dropwise added at 50-60° C. over 30 min.The mixture was stirred at the same temperature for 30 min. Ethylacetate (250 ml) and water (250 ml) were added to the reaction solutionand insoluble materials were removed. The resulting mixture was washedwith ethyl acetate (500 ml). After cooling the filtrate to 20-25° C., itwas partitioned 20% Citric acid (500 ml) was further dropwise addedslowly to the organic layer at 20-25° C. and the organic layer wasseparated. Water (50 ml) was added to the organic layer and 20% aqueouscitric acid solution was further added dropwise slowly at 20-25° C. toadjust its pH to 3.5. The mixture was partitioned and the organic layerwas washed successively with 5% brine, saturated aqueous sodiumhydrogencarbonate and 5% brine and concentrated under reduced pressure.The residue was dissolved in tetrahydrofuran (75 ml).

Separately, to a solution of sodium hydrogensulfite (26.18 g) in water(75 ml) were added tetrahydrofuran (350 ml) and isopropyl ether (150 ml)to give a mixed solution. To the mixed solution was added a half amountof the aforementioned tetrahydrofuran solution, and after stirring atroom temperature for 1.5 hrs., a ¼ amount of the aforementionedtetrahydrofuran solution was added and the mixture was stirred at roomtemperature for 30 min. Then, a ¼ amount of the aforementionedtetrahydrofuran solution was added and the mixture was stirred at roomtemperature for 2 hrs. The obtained mixture was cooled to 0-10° C. andstirred for 2 hrs. the precipitated crystals were filtrated and washedwith tetrahydrofuran/isopropyl ether=3/1 (200 ml) cooled to 0-10° C. togive sodiumhydroxy[2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)pyridin-3-yl]methanesulfonate.

This compound was suspended in ethyl acetate (400 ml) and 10% aqueoussodium carbonate solution (400 ml) and the mixture was stirred at 20-30°C. for 1 hr. The organic layer was washed with water (400 ml×3) andconcentrated under reduced pressure to give white crystals. Ethylacetate (50 ml) was added to the crystals, and after heating to 50-60°C., the mixture was stirred for 2 hrs. n-Hexane (100 ml) was dropwiseadded to the obtained mixture, and after stirring at 20-30° C. for 1hr., the mixture was cooled to 0-10° C. and stirred for 2 hrs. Theprecipitated crystals were filtrated, washed with n-hexane/ethylacetate=2/1 (100 ml) cooled to 0-10° C. in advance and dried (40° C.)under reduced pressure to give2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)nicotinaldehydeas white crystals.

¹H-NMR (CDCl₃, δ, 300 MHz); 2.43 (3H, s), 5.01 (2H, s), 5.47 (2H, s),7.01-7.06 (3H, m), 7.41-7.45 (5H, m), 7.99-8.03 (2H, m), 8.10-8.13 (1H,m), 8.37-8.40 (1H, m), 10.40 (1H, s).

Reference Example 157

To a mixture of acetonitrile (80 ml) and water (135 mg) were addedtrimethylsulfonium iodide (6.12 g) and then potassium hydroxide (3.36 g)with stirring2-({4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)nicotinaldehyde(6.0 g) was added to the mixture, and after heating, the mixture wasstirred at 40-50° C. for 4 hrs. The mixture was cooled to 0-10° C. andwater (32 ml) and then 20% citric acid were dropwise added to themixture at the same temperature to adjust to pH=7.1. The reactionsolution was concentrated under reduced pressure, and after evaporationof acetonitrile, extracted with t-butylmethyl ether (60 ml). The organiclayer was washed with water and concentrated under reduced pressuret-Butylmethyl ether (4 ml) was added to the residue and the mixture wasstirred at room temperature for 30 min. and n-hexane (12 ml) was added.The mixture was stirred at room temperature for 30 min., andt-butylmethyl ether/n-hexane=1/3 (8 ml) was added. The mixture wasstirred at room temperature for 15 min. and than under ice-cooling for40 min. The obtained crystals were filtrated, washed with t-butylmethylether/n-hexane=1/3 (8 ml) ice-cooled in advance and dried under reducedpressure to give2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)-3-oxyran-2-ylpyridineas white crystals.

¹H-NMR (CDCl₃, δ, 300 MHz); 2.45 (3H, s), 2.67 (1H, dd, J=2.6, 5.7 Hz),3.15 (1H, dd, J=4.2, 5.7 Hz), 4.15 (1H, dd, J=2.6, 4.2 Hz), 5.02 (2H,s), 5.41 (2H, s), 6.88-7.07 (3H, m), 7.41-7.4.7 (6H, m), 8.02-8.13 (3H,m).

Example 1

To a mixture of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(2.40 g), tetrahydrofuran (7 mL) and ethanol (7 mL) was added 1N aqueoussodium hydroxide solution (7.0 mL) and the mixture was stirred overnightat room temperature. The reaction mixture was concentrated, and waterand diethyl ether were added to the residue. Dilute hydrochloric acidwas added to acidify the aqueous layer, and the precipitated solid wascollected by filtration, and dried with air to give crystals (1.24 g,85%) of2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 159-160° C.

Example 2

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(2.42 g), ethyl 3-(3-hydroxyphenyl)propionate (1.35 g), anhydrouspotassium carbonate (0.97 g) and N,N-dimethylformamide (30 mL) wasstirred at 90° C. for 15 hrs. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (1.82 g, 55%) of ethyl3-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 90-91° C.

Example 3

To a mixture of ethyl3-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate(1.00 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added a 1Naqueous sodium hydroxide solution (4.2 mL) and the mixture was stirredat 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidifythe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated to give crystals (0.61 g, 66%) of3-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 157-158° C.

Example 4

To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.00 g), methyl 2-(2-ethoxy-5-hydroxyphenyl)acetate (0.60 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.14 g)under ice-cooling, and the mixture was stirred at room temperature for 2hrs. The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. After concentration of the organiclayer, the residue was subjected to silica gel column chromatography togive crystals (0.70 g, 70%) ofmethyl-2-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:4, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 82-83° C.

Example 5

To a mixture of methyl2-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.56 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added 1Naqueous sodium hydroxide solution (2.2 mL) and the mixture was stirredat 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidifythe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated to give crystals (0.45 g, 87%) of2-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 122-123° C.

Example 6

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.44 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (1.0 g),anhydrous potassium carbonate (0.58 g) and N,N-dimethylformamide (50 mL)was stirred at 90° C. for 2 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give ethyl3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4oxazolyl)methoxy]benzyloxy]phenyl]propionateas an oil (1.57 g, 72%) from a fraction eluted with ethyl acetate-hexane(1:6, v/v).

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.0 Hz), 1.38 (3H, t, J=7.0 Hz), 2.44(3H, s), 2.56-2.64 (2H, m), 2.90-2.98 (2H, m), 3.96 (2H, q, J=7.0 Hz),4.11 (2H, q, J=7.0 Hz), 4.97 (2H, s), 5.01 (2H, s), 6.65-6.84 (3H, m),7.00-7.06 (2H, m), 7.26-7.47 (5H, m), 7.99-8.05 (2H, m).

Example 7

To a mixture of ethyl3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate(0.58 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueoussodium hydroxide solution (2.2 mL) and the mixture was stirred at roomtemperature for 2 hrs. 1N Hydrochloric acid and water were added toacidify the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated to give crystals (0.46 g,85%) of3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 129-130° C.

Example 8

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.80 g), methyl 4-hydroxyphenylacetate (0.42 g), anhydrous potassiumcarbonate (0.35 g) and N,N-dimethylformamide (20 mL) was stirred at 90°C. for 2 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was subjected to silica gel column chromatography to givecrystals (0.70 g, 63%) of methyl2-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 93-94° C.

Example 9

To a mixture of methyl2-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.55 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1Naqueous sodium hydroxide solution (2.5 mL) and the mixture was stirredat room temperature for 2 hrs. 1N Hydrochloric acid and water were addedto acidify the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated to give crystals(0.45 g, 87%) of2-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from tetrahydrofuran-hexane gave colorless prismcrystals. melting point: 166-167° C.

Example 10

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.91 g), ethyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassiumcarbonate (0.76 g) and N,N-dimethylformamide (20 mL) was stirred at 90°C. for 2 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was subjected to silica gel column chromatography to give ethyl2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetateas an oil (1.35 g, 54%) from a fraction eluted with ethyl acetate-hexane(1:4, v/v).

¹H-NMR (CDCl₃) δ: 1.19 (3H, t, J=7.0 Hz), 2.44 (3H, s), 3.65 (2H, s),4.10 (2H, q, J=7.0 Hz), 5.00 (2H, s), 5.02 (2H, s), 6.89-7.04 (4H, m),7.18-7.46 (7H, m), 7.99-8.04 (2H, m).

Example 11

To a mixture of ethyl2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(1.35 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueoussodium hydroxide solution (6 mL) and the mixture was stirred at roomtemperature for 2 hrs. 1N Hydrochloric acid and water were added toacidify the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated to give crystals (0.98 g,76%) of2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 153-154° C.

Example 12

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.60 g), methyl 3-(2-hydroxyphenyl)propionate (0.345 g), anhydrouspotassium carbonate (0.529 g) and N,N-dimethylformamide (7 mL) wasstirred at room temperature for 18 hrs., and further at 70° C. for 5hrs. The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue wassubjected to silica gel column chromatography to give methyl3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionateas an oil (0.61 g, 70%) from a fraction eluted with ethyl acetate-hexane(1:3, v/v).

NMR (CDCl₃) δ: 2.45 (3H, s), 2.59-2.68 (2H, m), 2.94-3.03 (2H, m), 3.64(3H, s), 5.01 (2H, s), 5.03 (2H, s), 6.84-6.93 (2H, m), 7.03 (2H, d,J=8.6 Hz), 7.13-7.23 (2H, m), 7.34-7.48 (5H, m), 7.99-8.05 (2H, m).

Example 13

A mixture of methyl3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate(0.54 g), lithium hydroxide monohydrate (0.0743 g), tetrahydrofuran (6mL), water (4 mL) and methanol (4 mL) was stirred at room temperaturefor 1.5 hrs. 1N Hydrochloric acid (1.8 mL) was added to acidify thereaction mixture and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals of3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals (0.49 g, 94%). melting point: 98-99° C.

Example 14

Methyl2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(1.00 g), tetramethyltin (0.73 g), tetrakis(triphenylphosphine)palladium(0.11 g) and toluene (50 mL) were stirred with heating under refluxunder an argon atmosphere for 40 hrs. The reaction mixture wasconcentrated and the residue was subjected to silica gel columnchromatography to give crystals (0.28 g, 32%) of methyl2-[5-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 80-81° C.

Example 15

To a mixture of methyl2-[5-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.22 g), tetrahydrofuran (1 mL) and methanol (1 mL) was added a 1Naqueous sodium hydroxide solution (1 mL) and the mixture was stirred at50° C. for 1.5 hrs. 1N Hydrochloric acid (1 mL) and water were added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.16 g, 76%) of2-[5-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 115-116° C.

Example 16

To a mixture of2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile(0.30 g) and ethanol (3 mL) was added a 4N aqueous potassium hydroxidesolution (1 mL) and the mixture was stirred with heating under refluxfor 24 hrs. 1N Hydrochloric acid and water were added to acidify thereaction mixture, and the mixture was extracted with ethylacetate-tetrahydrofuran. The organic layer was washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was subjected to silica gel column chromatography togive crystals (0.05 g, 16%) of2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid from a fraction eluted with ethyl acetate-hexane (5:1, v/v).Recrystallization from tetrahydrofuran-hexane gave pale-brown prismcrystals. melting point: 194-195° C.

Example 17

To a mixture of[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (1.0 g),methyl 2-(5-chloro-2-hydroxyphenyl)acetate (0.74 g), triphenylphosphine(1.08 g) and tetrahydrofuran (50 mL) was dropwise added a solution (40%,1.79 g) of diethyl azodicarboxylate in toluene at room temperature, andthe mixture was stirred for 15 hrs. The reaction mixture wasconcentrated and the residue was subjected to silica gel columnchromatography to give methyl2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetateas an oil (0.68 g, 42%) from a fraction eluted with ethyl acetate-hexane(1:6, v/v).

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 3.61 (2H, s), 3.63 (3H, s), 4.99 (2H,s), 5.00 (2H, s), 6.82-6.87 (1H, m), 7.00-7.04 (2H, m), 7.17-7.22 (2H,m), 7.29-7.33 (2H, m), 7.42-7.47 (3H, m), 7.99-8.04 (2H, m).

Example 18

To a mixture of methyl2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.68 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1Naqueous sodium hydroxide solution (2.8 mL) and the mixture was stirredat 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added tothe reaction mixture, and the precipitated solid was collected byfiltration, and dried with air to give crystals (0.63 g, 97%) of2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 160-161° C.

Example 19

To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(4.58 g), methyl 2-(5-bromo-2-hydroxyphenyl)acetate (3.0 g) andN,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 0.54g) under ice-cooling, and the mixture was stirred at room temperaturefor 15 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. After concentration of theorganic layer, the residue was subjected to silica gel columnchromatography to give crystals (4.46 g, 70%) of methyl2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 100-101° C.

Example 20

To a mixture of methyl2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.80 g), tetrahydrofuran (3 mL) and methanol-(3 mL) was added a 1Naqueous sodium hydroxide solution (3 mL) and the mixture was stirred at50° C. for 1.5 hrs. 1N Hydrochloric acid (3 mL) and water were added tothe reaction mixture, and the precipitated solid was collected byfiltration and dried with air to give crystals (0.63 g, 83%) of2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 162-163° C.

Example 21

Methyl2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(1.20 g), phenylboronic acid (0.30 g),tetrakis(triphenylphosphine)palladium (0.14 g), 2M aqueous sodiumcarbonate solution (3.7 mL), methanol (5 mL), and toluene (20 mL) werestirred with heating under reflux for 24 hrs under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, washed withsaturated brine and dried over anhydrous magnesium sulfate. Afterconcentration of the organic layer, the residue was subjected to silicagel column chromatography to give crystals (0.89 g, 74%) of methyl2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 111-112° C.

Example 22

To a mixture of methyl2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]acetate(0.65 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1Naqueous sodium hydroxide solution (2.8 mL) and the mixture was stirredat 50° C. for 1.5 hrs. 1N Hydrochloric acid (3 mL) and water were addedto the reaction mixture, and the precipitated solid was collected byfiltration and dried with air to give crystals (0.65 g, 92%) of2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 102-103° C.

Example 23

To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.54 g), methyl 2-(2-hydroxy-5-methoxyphenyl)acetate (0.80 g) andN,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.18g) under ice-cooling, and the mixture was stirred at room temperaturefor 15 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate. After concentration of theorganic layer, the residue was subjected to silica gel columnchromatography to give crystals (1.22 g, 63%) of methyl2-[5-methoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 160-161° C.

Example 24

To a mixture of methyl2-[5-methoxy-2-[-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.98 g), tetrahydrofuran (4 mL) and methanol (4 mL) was added a 1Naqueous sodium hydroxide solution (4.2 mL) and the mixture was stirredat 50° C. for 15 hrs. 1N Hydrochloric acid (4.2 mL) and water were addedto the reaction mixture, and the precipitated solid was collected byfiltration and dried with air to give crystals (0.90 g, 94%) of2-[5-methoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 134-136° C.

Example 25

To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.72 g), methyl 2-(5-ethoxy-2-hydroxyphenyl)acetate (0.40 g) andN,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.08g) under ice-cooling and the mixture was stirred at room temperature for15 hrs. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. After concentration of theorganic layer, the residue was subjected to silica gel columnchromatography to give methyl2-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetateas an oil (0.56 g, 60%) from a fraction eluted with ethyl acetate-hexane(1:4, v/v).

NMR (CDCl₃) δ: 1.38 (3H, t, J=7.0 Hz), 2.44 (3H, s), 3.62 (5H, s), 3.98(2H, q, J=7.0 Hz), 4.95 (2H, s), 5.00 (2H, s), 6.73-6.89 (3H, m),6.99-7.04 (2H, m), 7.25-7.47 (5H, m), 7.99-8.04 (2H, m).

Example 26

To a mixture of methyl2-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.56 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1Naqueous sodium hydroxide solution (2.2 mL) and the mixture was stirredat 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidifythe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.45 g, 87%) of2-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 122-123° C.

Example 27

To a mixture of2-[5-benzyloxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile(0.18 g), tetrahydrofuran (0.5 mL) and ethanol (3 mL) was added a 4Naqueous potassium hydroxide solution (1 mL), and the mixture was stirredwith heating under reflux for 1 hr. 1N Hydrochloric acid and water wereadded to acidify the reaction mixture, and the mixture, was extractedwith ethyl acetate-tetrahydrofuran. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (0.03 g, 17%) of2-[5-benzyloxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid from a fraction eluted with ethyl acetate-hexane (2:3, v/v).Recrystallization from tetrahydrofuran-hexane gave colorless prismcrystals. melting point: 140-141° C.

Example 28

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.44 g), ethyl 3-(5-ethoxy-2-hydroxyphenyl)propionate (1.0 g),anhydrous potassium carbonate (0.58 g) and N,N-dimethylformamide (50 mL)was stirred at 90° C. for 2 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give ethyl3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionateas an oil (1.57 g, 72%) from a fraction eluted with ethyl acetate-hexane(1:6, v/v).

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.0 Hz), 1.38 (3H, t, J=7.0 Hz), 2.44(3H, s), 2.56-2.64 (2H, m), 2.90-2.98 (2H, m), 3.96 (2H, q, J=7.0 Hz),4.11 (2H, q, J=7.0 Hz), 4.97 (2H, s), 5.01 (2H, s), 6.65-6.84 (3H, m),7.00-7.06 (2H, m), 7.26-7.47 (5H, m), 7.99-8.05 (2H, m).

Example 29

To a mixture of ethyl3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate(1.56 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1Naqueous sodium hydroxide solution (6.0 mL), and the mixture was stirredat 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidifythe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (1.14 g, 78%) of3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 115-116° C.

Example 30

To a mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.70 g), methyl 2-(2-hydroxyphenyl)acetate (0.33 g) andN,N-dimethylformamide (10 mL) was added sodium hydride (60%, oil, 0.09g) under ice-cooling and the mixture was stirred at room temperature for15 hrs. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. After concentration of theorganic layer, the residue was subjected to silica gel columnchromatography to give methyl2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetateas an oil (0.50 g, 56%) from a fraction eluted with ethyl acetate-hexane(1:4, v/v).

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 3.65 (3H, s), 3.69 (2H, s), 5.02 (2H,s), 5.08 (2H, s), 6.88-7.34 (8H, m), 7.41-7.45 (3H, m), 7.99-8.04 (2H,m).

Example 31

To a mixture of methyl2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.50 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1Naqueous sodium hydroxide solution (2.0 mL) and the mixture was stirredat 50° C. for 1 hr. 1N Hydrochloric acid (2 mL) and water were added toacidify the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated: to give crystals (0.41 g,87%) of2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from methyl acetate-hexane gave colorless prismcrystals. melting point: 117-118° C.

Example 32

A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.21 g), methyl 2-(3-hydroxyphenyl)acetate (0.60 g), anhydrouspotassium carbonate (0.65 g) and N,N-dimethylformamide (10 mL) wasstirred at 80° C. for 5 hrs. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washedsuccessively with dilute hydrochloric acid and saturated brine, driedover anhydrous magnesium sulfate and concentrated. The obtained residuewas subjected to silica gel column chromatography to give an oil from afraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture ofthe obtained oil, tetrahydrofuran (5 mL) and methanol (5 mL) was added a1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirredat room temperature for 2 hrs. The reaction mixture was concentrated,and dilute hydrochloric acid was added to acidify the residue. Theprecipitated solid was collected by filtration and dried with air togive crystals (1.40 g, 90%) of2-[[3-[3-(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 101-102° C.

Example 33

A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g),anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL)was stirred at 80° C. for 5 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedsuccessively with dilute hydrochloric acid and saturated brine, driedover, anhydrous magnesium sulfate and concentrated. The obtained residuewas subjected to silica gel column chromatography to give an oil from afraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture ofthe obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirredat room temperature for 2 hrs. The reaction mixture was concentrated,and dilute hydrochloric acid was added to acidify the residue. Theprecipitated solid was collected by filtration and dried with air togive crystals (0.89 g, 95%) of3-[2-ethoxy-5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 136-137° C.

Example 34

A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.21 g), methyl 2-(3-hydroxyphenyl)acetate (0.60 g), anhydrouspotassium carbonate (0.65 g) and N,N-dimethylformamide (10 mL) wasstirred at 80° C. for 5 hrs. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washedsuccessively with dilute hydrochloric acid and saturated brine, driedover anhydrous magnesium sulfate and concentrated. The obtained residuewas subjected to silica gel column chromatography to give an oil from afraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture ofthe obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirredat room temperature for 2 hrs. The reaction mixture was concentrated,and dilute hydrochloric acid was added to acidify the residue. Theprecipitated solid was collected by filtration and dried with air togive crystals (1.37 g, 88%) of2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 104-105° C.

Example 35

A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g),anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL)was stirred at 80° C. for 5 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedsuccessively with dilute hydrochloric acid and saturated brine, driedover anhydrous magnesium sulfate and concentrated. The obtained residuewas subjected to silica gel column chromatography to give an oil from afraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture ofthe obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirredat room temperature for 2 hrs. The reaction mixture was concentrated,and dilute hydrochloric acid was added to acidify the residue. Theprecipitated solid was collected by filtration and dried with air togive crystals (0.89 g, 95%) of3-[2-ethoxy-5-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 146-147° C.

Example 36

To a mixture of2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile(0.20 g), tetrahydrofuran (0.5 mL) and ethanol (1 mL) was added a 2Naqueous sodium hydroxide solution (1.5 mL) and the mixture was stirredwith heating under reflux for 10 hrs. 1N Hydrochloric acid (3 mL) andwater were added to the reaction mixture, the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated. The obtained residuewas subjected to silica gel column chromatography to give crystals (0.08g, 38%) of2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid from a fraction eluted with ethyl acetate-hexane (1:1, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 144-145° C.

Example 37

To a mixture of2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]acetonitrile(0.55 g), tetrahydrofuran (1 mL) and ethanol (4 mL) was added a 2Naqueous sodium hydroxide solution (4 mL) and the mixture was stirredwith heating under reflux for 12 hrs. 1N Hydrochloric acid (8 mL) andwater were added to the reaction mixture, and the precipitated solid wascollected by filtration and dried with air to give crystals (0.35 g,47%) of2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]aceticacid. Recrystallization from tetrahydrofuran-hexane gave colorless prismcrystals. melting point: 115-116° C. (dec.)

Example 38

To a mixture of2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile(0.66 g), tetrahydrofuran (1 mL) and ethanol (5 mL) was added a 2Naqueous sodium hydroxide solution (5 mL) and the mixture was stirredwith heating under reflux for 8 hrs. 1N Hydrochloric acid (10 mL) andwater were added to the reaction mixture, and the precipitated solid wascollected by filtration and dried with air to give crystals (0.67 g,97%) of2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid. Recrystallization from tetrahydrofuran-hexane gave pale-brownprism crystals. melting point: 139-140° C.

Example 39

To a mixture of2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]acetonitrile(0.96 g), tetrahydrofuran (5 mL) and ethanol (15 mL) was added a 4Naqueous sodium hydroxide solution (7 mL), and the mixture was stirredwith heating under reflux for 4.5 days. 1N Hydrochloric acid and waterwere added to acidify the reaction mixture, and the mixture wasextracted with ethyl acetate-tetrahydrofuran. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (0.52 g, 51%) of2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]aceticacid from a fraction eluted with ethyl acetate-hexane (1:1, v/v).Recrystallization from ethyl acetate-hexane gave pale-yellow prismcrystals. melting point: 187-188° C.

Example 40

To a mixture of5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolyl)methoxypyridine (0.91 g),methyl 2-(2-hydroxyphenyl)acetate (0.44 g) and N,N-dimethylformamide (20mL) was added sodium hydride (60%, oil, 0.12 g) under ice-cooling, andthe mixture was stirred at room temperature for 15 hrs. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. After concentration of the organic layer, the residuewas subjected to silica gel column chromatography to give methyl2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetateas an oil (0.81 g, 70%) from a fraction eluted with ethyl acetate-hexane(1:4, v/v).

¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 3.62 (3H, s), 3.64 (2H, s), 5.02 (2H,s), 5.32 (2H, s), 6.85 (1H, d, J=8.6 Hz), 6.92-6.99 (2H, m), 7.19-7.31(2H, m), 7.39-7.46 (3H, m), 7.65 (1H, dd, J=8.6, 2.2 Hz), 8.01-8.06 (2H,m), 8.21 (1H, d, J=2.2 Hz).

Example 41

To a mixture of methyl2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate(0.81 g), tetrahydrofuran (4 mL) and methanol (4 mL) was added a 1Naqueous sodium hydroxide solution (3.6 mL) and the mixture was stirredat 50° C. for 1 hr. 1N Hydrochloric acid (3.7 mL) and water were addedto the reaction mixture, and the precipitated solid was collected byfiltration and dried with air to give crystals (0.75 g, 97%) of2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 123-125° C.

Example 42

To a mixture of[5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridyl]methanol (1.50 g),methyl 2-(2-hydroxyphenyl)acetate (0.76 g), triphenylphosphine (1.44 g)and tetrahydrofuran (50 mL) was dropwise added a solution (40%, 2.39 g)of diethyl azodicarboxylate in toluene at room temperature, and themixture was stirred for 15 hrs. The reaction mixture was concentratedand the residue was subjected to silica gel column chromatography togive crude crystals from a fraction eluted with ethyl acetate-hexane(1:1, v/v) which crude crystals were further subjected to silica gelcolumn chromatography to give crystals (1.24 g, 61%) of methyl2-[2-[[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetatefrom a fraction eluted with tetrahydrofuran-hexane (3:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 77-78° C.

Example 43

To a mixture of methyl2-[2-[[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate(1.05 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1Naqueous sodium hydroxide solution (5 mL) and the mixture was stirred at50-60° C. for 1.5 hrs. 1N Hydrochloric acid (5 mL) and water were addedto the reaction mixture, and the precipitated solid was collected byfiltration and dried with air to give crystals (1.00 g, 97%) of2-[2-[[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]aceticacid. Recrystallization from tetrahydrofuran-hexane gave colorless prismcrystals. melting point: 207-208° C.

Example 44

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.50 g), ethyl 3-(4-hydroxyphenyl)propionate (0.31 g), anhydrouspotassium carbonate (0.22 g) and N,N-dimethylformamide (15 mL) wasstirred at 90° C. for 2 hrs. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (0.38 g, 51%) of ethyl3-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 105-106° C.

Example 45

To a mixture of ethyl3-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate(0.30 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1Naqueous sodium hydroxide solution (1.3 mL) and the mixture was stirredat room temperature for 2 hrs. 1N Hydrochloric acid and water were addedto acidify the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated to give crystals (0.25g, 89%) of3-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from tetrahydrofuran-hexane gave colorless prismcrystals. melting point: 177-178° C.

Example 46

A mixture of ethyl3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]-2-propenoate(1.51 g), platinum oxide (0.18 g), ethanol (5 mL) and tetrahydrofuran(10 mL) was stirred at room temperature overnight under a hydrogenatmosphere. The catalyst was filtered off, and the filtrate wasconcentrated to give crystals (1.36 g, 90%) of ethyl3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]propionate.Recrystallization from acetone-hexane gave colorless needle crystals.melting point: 86-87° C.

Example 47

To a mixture of ethyl3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]propionate(1.16 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1Naqueous sodium hydroxide solution (5 mL) and the mixture was stirred atroom temperature for 2 hrs. The reaction mixture was concentrated, anddilute hydrochloric acid was added to acidify the residue. Theprecipitated solid was collected by filtration and dried with air togive crystals (1.03 g, 94%) of3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]propionicacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 161-162° C.

Example 48

A mixture of4-(4-chloromethyl-3-methoxyphenoxymethyl)-2-phenyl-5-methyloxazole (2.08g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassiumcarbonate (1.65 g) and N,N-dimethylformamide (15 mL) was stirredovernight at room temperature. The reaction mixture was poured intodilute hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated. To a mixture of the obtained residue,tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1N aqueoussodium hydroxide solution (10 mL) and the mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was concentrated, and dilutehydrochloric acid was added to the residue. The precipitated solid wascollected by filtration and dried with air to give crystals (1.36 g,49%) of2-[2-[3-methoxy-4-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from acetone-hexane gave colorless needlecrystals. melting point: 165-166° C.

Example 49

To a mixture of[4-methoxy-3-[(5-methoxy-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol(0.95 g), methyl 2-(2-hydroxyphenyl)acetate (0.50 g), triphenylphosphine(0.95 g) and tetrahydrofuran (15 mL) was dropwise added a solution (40%,1.74 g) of diethyl azodicarboxylate in toluene at room temperature, andthe mixture was stirred overnight. The reaction mixture was concentratedand the residue was subjected to silica gel column chromatography togive an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v).To a mixture of the obtained oil, tetrahydrofuran (10 mL) and ethanol(10 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and themixture was stirred overnight at room temperature. The reaction mixturewas neutralized with 1N hydrochloric acid (5 mL), extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated. The residue was subjectedto silica gel column chromatography to give2-[2-[4-methoxy-3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid from a fraction eluted with ethyl acetate-hexane (1:1, v/v).Recrystallization with ethanol-hexane gave colorless plate crystals(0.52 g, 37%). melting point: 154-155° C.

Example 50

A mixture of 4-(4-chloromethylphenoxymethyl)-2-(2-furyl)-5-methyloxazole(1.84 g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrouspotassium carbonate (1.66 g) and N,N-dimethylformamide (15 mL) wasstirred at room temperature overnight. The reaction mixture was pouredinto dilute hydrochloric acid and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated. To a mixture of the obtainedresidue, tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1Naqueous sodium hydroxide solution (10 mL) and the mixture was stirred atroom temperature for 2 hrs. The reaction mixture was concentrated, anddilute hydrochloric acid was added to the residue. The precipitatedsolid was collected by filtration and dried with air to give crystals(2.08 g, 82%) of2-[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 167-168° C.

Example 51

A mixture of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole (1.95 g),methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassiumcarbonate (0.85 g) and N,N-dimethylformamide (15 mL) was stirredovernight at room temperature. The reaction mixture was poured intodilute hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated. To a mixture of the obtained residue,tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1N aqueoussodium hydroxide solution (10 mL) and the mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was concentrated, and dilutehydrochloric acid was added to the residue. The precipitated solid wascollected by filtration and dried with air to give crystals (0.76 g,29%) of 2-[2-[4-[(2-phenyl-4-thiazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 115-116° C.

Example 52

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenylthiazole(2.13 g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrouspotassium carbonate (1.65 g) and N,N-dimethylformamide (15 mL) wasstirred overnight at room temperature. The reaction mixture was pouredinto dilute hydrochloric acid and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated. To a mixture of the obtainedresidue, tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1Naqueous sodium hydroxide solution (10 mL) and the mixture was stirred atroom temperature for 2 hrs. The reaction mixture was concentrated, anddilute hydrochloric acid was added to the residue. The precipitatedsolid was collected by filtration and dried with air to give crystals(1.19 g, 44%) of2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 122-123° C.

Example 53

A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(8.37 g), 2-(3-hydroxyphenyl)acetic acid (2.02 g), anhydrous potassiumcarbonate (7.39 g) and N,N-dimethylformamide (30 mL) was stirredovernight at room temperature. The reaction mixture was poured intodilute hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was subjected to silicagel column chromatography to give crystals (8.37 g, 89%) of4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:9, v/v).Recrystallization from acetone-hexane gave colorless prism crystals.melting point: 90-91° C.

Example 54

To a mixture of2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthaldehyde(5.48 g), triethyl phosphonoacetate (2.98 g) and N,N-dimethylformamide(50 ml) was added sodium hydride (0.51 g) under ice-cooling. Thereaction mixture was stirred at room temperature for 2 hrs. The reactionmixture was poured into iced water, and the precipitated solid wascollected by filtration and dried with air to give crystals (5.54 g,88%) of ethyl3-(2-(4-((5-methyl-2-phenyl-4-oxazolyl)methoxy)benzyloxy)-1-naphthyl)-2-propenoate.Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 73-74° C.

Example 55

To a mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.04 g), methyl 2-(2-hydroxyphenyl)acetate (0.50 g) andN,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.13g) under ice-cooling, and the mixture was stirred at room temperaturefor 15 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. After concentration of theorganic layer, the residue was subjected to silica gel columnchromatography to give methyl2-[2-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetateas an oil (0.71 g, 53%) from a fraction eluted with ethyl acetate-hexane(1:6, v/v).

¹H-NMR (CDCl₃) δ: 2.40 (3H, s), 3.63 (3H, s), 3.70 (2H, s), 5.06 (2H,s), 5.16 (2H, s), 6.86-7.34 (7H, m), 7.42-7.49 (4H, m), 7.98-8.03 (2H,m).

Example 56

To a mixture of methyl2-[2-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.71 g), tetrahydrofuran (3.0 mL) and methanol (3.0 mL) was added a 1Naqueous sodium hydroxide solution (3.2 mL) and the mixture was stirredat 50° C. for 1.5 hrs. 1N Hydrochloric acid (3.2 mL) and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated to give crystals (0.62 g,90%) of2-[2-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 145-146° C.

Example 57

To a mixture of4-[2-(4-chloromethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (0.85 g),methyl 2-(2-hydroxyphenyl)acetate (0.40 g) and N,N-dimethylformamide (30mL) was added sodium hydride (60%, oil, 0.11 g) under ice-cooling, andthe mixture was stirred at room temperature for 15 hrs. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. After concentration of the organic layer, the residuewas subjected to silica gel column chromatography to give methyl2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]phenyl]acetateas an oil (0.57 g, 57%) from a fraction eluted with ethyl acetate-hexane(1:6, v/v).

¹H-NMR (CDCl₃) δ: 2.38 (3H, s), 2.99 (2H, t, J=6.6 Hz), 3.62 (3H, s),3.65 (2H, s), 4.25 (2H, t, J=6.6 Hz), 4.99 (2H, s), 6.87-6.96 (4H, m),7.17-7.36 (4H, m), 7.40-7.48 (3H, m), 7.93-8.00 (2H, m).

Example 58

To a mixture of methyl2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]phenyl]acetate(0.57 g), tetrahydrofuran (3.0 mL) and methanol (3.0 mL) was added a 1Naqueous sodium hydroxide solution (2.4 mL) and the mixture was stirredat 50° C. for 1.5 hrs. 1N Hydrochloric acid (2.4 mL) and water wereadded to the reaction mixture, and the precipitated solid was collectedby filtration and dried with air to give crystals (0.51 g, 96%) of2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 141-142° C.

Example 59

To a mixture of t-butyl4-(hydroxymethyl)phenyl[(5-methyl-2-phenyl-4-oxazolyl)methyl]carbamate(1.0 g), triethylamine (1.01 g) and ethyl acetate (50 mL) was addedmethanesulfonyl chloride (1.15 g) at 0° C. The reaction mixture wasstirred at room temperature for 20 hrs., diluted with ethyl acetate andwashed successively with a saturated aqueous sodium hydrogencarbonateand saturated brine. The mixture was dried over anhydrous magnesiumsulfate and concentrated to give pale-yellow crystals. To a mixture ofthe obtained crystals, methyl 2-(2-hydroxyphenyl)acetate (0.55 g) andN,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.14g) at 0° C. The mixture was stirred at room temperature for 3 hrs. Tothe reaction mixture was added water and the mixture was extracted withethyl acetate. The organic layer was washed successively with water, 2Naqueous sodium hydroxide solution and saturated brine, and dried overanhydrous magnesium sulfate. After concentration of the organic layer,the residue was subjected to silica gel column chromatography to givecrystals (0.82 g, 60%) of methyl2-[2-[4-[(t-butoxycarbonyl)[(5-methyl-2-phenyl-4-oxazolyl)methyl]amino]benzyloxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 85-86° C.

Example 60

To a mixture of methyl2-[2-[4-[(t-butoxycarbonyl)[(5-methyl-2-phenyl-4-oxazolyl)methyl]amino]benzyloxy]phenyl]acetate(0.30 g), tetrahydrofuran (1.0 mL) and methanol (1.0 mL) was added a 1Naqueous sodium hydroxide solution (1.0 mL) and the mixture was stirredat 50° C. for 1 hr. 1N Hydrochloric acid (1.0 mL) and water were addedto the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated to give2-[2-[4-[(t-butoxycarbonyl)[(5-methyl-2-phenyl-4-oxazolyl)methyl]amino]benzyloxy]phenyl]aceticacid as a colorless amorphous compound (0.19 g, 66%).

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.38 (3H, s), 3.57 (2H, s), 4.70 (2H,s), 5.09 (2H, s), 6.98-7.26 (8H, m), 7.40-7.42 (3H, m), 7.90-8.00 (2H,m). Elemental analysis: for C₃₁H₃₂N₂O₆ Calculated, C: 70.44; H, 6.10; N,5.30. Found, C: 70.22; H, 6.24; N, 5.06.

Example 61

A mixture of4-(chloromethyl)-2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]pyridine(0.472 g), methyl 2-(3-hydroxyphenyl)acetate (0.249 g), anhydrouspotassium carbonate (0.415 g) and N,N-dimethylformamide (10 mL) wasstirred at 60° C. for 3 hrs. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give methyl2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]acetateas a colorless oil (0.597 g, 90%) from a fraction eluted with ethylacetate-hexane (1:2, v/v).

¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 3.59 (2H, s), 3.68 (3H, s), 5.02 (2H,s), 5.31 (2H, s), 6.79-6.84 (4H, m), 6.94 (1H, d, J=5.2 Hz), 7.23 (1H,t, J=8.0 Hz), 7.39-7.45 (3H, m), 7.98-8.05 (2H, m), 8.16 (1H, d, J=5.2Hz).

Example 62

To a mixture of methyl2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]acetate(0.596 g), tetrahydrofuran (6.0 mL) and methanol (6.0 mL) was added a 1Naqueous sodium hydroxide solution (3.0 mL), and the mixture was stirredat room temperature for 1 hr. 1N Hydrochloric acid (3.0 mL) and waterwere added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated to give crystals of2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]aceticacid. Recrystallization from ethanol-hexane gave colorless prismcrystals (0.566 g, 98%). melting point: 148-149° C.

Example 63

A mixture of2-(chloromethyl)-6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]pyridine (0.96g), methyl 2-(3-hydroxyphenyl)acetate (0.50 g), anhydrous potassiumcarbonate (0.52 g) and N,N-dimethylformamide (15 mL) was stirred at 80°C. for 5 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was subjected to silica gel column chromatography to give methyl2-[3-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-2-pyridylmethoxy]phenyl]acetateas a colorless oil (1.17 g, 87%) from a fraction eluted with ethylacetate-hexane (1:1, v/v).

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 3.61 (2H, s), 3.69 (3H, s), 5.11 (2H,s), 5.32 (2H, s), 6.70-6.80 (1H, m), 6.84-6.98 (3H, m), 7.04-7.12 (1H,m), 7.17-7.32 (1H, m), 7.36-7.48 (3H, m), 7.52-7.65 (1H, m), 7.96-8.10(2H, m).

Example 64

To a mixture of methyl2-[3-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-2-pyridyl]methoxy]phenyl]acetate(1.10 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1Naqueous sodium hydroxide solution (5.0 mL) and the mixture was stirredat room temperature for 3 hrs. The reaction mixture was concentrated,and water and dilute hydrochloric acid were added to acidify theresidue. The precipitated solid was collected by filtration and driedwith air to give crystals (0.85 g, 80%) of2-[3-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-2-pyridyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 97-98° C.

Example 65

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.19 g), ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate (0.76 g),anhydrous potassium carbonate (0.44 g) and N,N-dimethylformamide (30 mL)was stirred at 90° C. for 2 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give crystals (1.35 g, 82%) of ethyl3-[2-ethoxy-4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 64-65° C.

Example 66

To a mixture of ethyl3-[2-ethoxy-4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate(1.20 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1Naqueous sodium hydroxide solution (5.0 mL) and the mixture was stirredat room temperature for 2 hrs. 1N Hydrochloric acid and water were addedto acidify the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated to give crystals (1.09g, 97%) of3-[2-ethoxy-4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 135-136° C.

Example 67

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.73 g), 3-(4-mercaptophenyl)propionic acid (1.00 g), triethylamine(1.22 g) and N,N-dimethylformamide (20 mL) was stirred at roomtemperature for 2 hrs. The reaction mixture was poured into water,acidified with 2N hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous magnesiumsulfate and concentrated to give crystals of3-[4-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl]sulfanyl]phenyl]propionicacid. Recrystallization from ethyl acetate gave colorless prism crystals(1.85 g, 73%). melting point: 157-158° C.

Example 68

A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.89 g), methyl 2-(4-hydroxyphenyl)acetate (0.50 g), anhydrouspotassium carbonate (0.49 g) and N,N-dimethylformamide (15 mL) wasstirred at room temperature for 3 hrs. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer waswashed successively with dilute hydrochloric acid and saturated brine,dried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was subjected to silica gel column chromatography to givecolorless crystals from a fraction eluted with ethyl acetate-hexane(1:4, v/v). To a mixture of the obtained crystal, tetrahydrofuran (6 mL)and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6mL) and the mixture was stirred at room temperature for 2 hrs. Dilutehydrochloric acid was added to acidify the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated to give crystals (1.13 g, 93%) of2-[4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 179-180° C.

Example 69

A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.98 g), methyl 2-(4-hydroxyphenyl)acetate (0.51 g), anhydrouspotassium carbonate (0.52 g), and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 3 hrs. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer waswashed successively with dilute hydrochloric acid and saturated brine,dried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was subjected to silica gel column chromatography to give an oilfrom a fraction eluted with ethyl acetate-hexane (1:4, v/v). To amixture of the obtained oil, tetrahydrofuran (6 mL), and methanol (6 mL)was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixturewas stirred at room temperature for 2 hrs. Dilute hydrochloric acid wasadded to acidify the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated to give crystals(1.00 g, 76%) of2-[4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 173-174° C.

Example 70

A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.78 g), ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate (0.50 g),anhydrous potassium carbonate (0.29 g) and N,N-dimethylformamide (20 mL)was stirred at 90° C. for 2 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give ethyl3-[2-ethoxy-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionateas a colorless oil (0.94 g, 87%) from a fraction eluted with ethylacetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.0 Hz), 1.40 (3H, t, J=7.0 Hz), 2.43(3H, s), 2.52-2.60 (2H, m), 2.82-2.91 (2H, m), 3.98 (2H, q, J=7.0 Hz),4.11 (2H, q, J=7.0 Hz), 5.01 (4H, s), 6.41-6.49 (2H, m), 6.94-7.11 (4H,m), 7.26-7.47 (4H, m), 7.98-8.04 (2H, m).

Example 71

To a mixture of ethyl3-[2-ethoxy-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate(0.94 g), tetrahydrofuran (4 mL) and ethanol (4 mL) was added a 1Naqueous sodium hydroxide solution (3.6 mL) and the mixture was stirredat 50° C. for 2 hrs. 1N Hydrochloric acid and water were added toacidify the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated to give crystals (0.75 g,85%) of3-[2-ethoxy-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 122-123° C.

Example 72

A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.50 g), ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate (0.31 g),anhydrous potassium carbonate (0.18 g) and N,N-dimethylformamide (10 mL)was stirred at 90° C. for 2 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give ethyl3-[2-ethoxy-4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionateas a colorless oil (0.62 g, 93%) from a fraction eluted with ethylacetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.0 Hz), 1.37 (2H, t, J=7.0 Hz), 2.38(3H, s), 2.51-2.59 (2H, m), 2.80-2.88 (2H, m), 3.96 (2H, q, J=7.0 Hz),4.11 (2H, q, J=7.0 Hz), 5.07 (2H, s), 5.09 (2H, s), 6.42-6.50 (2H, m),6.96-7.09 (3H, m), 7.26-7.48 (5H, m), 7.97-8.02 (2H, m).

Example 73

To a mixture of ethyl3-[2-ethoxy-4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate(0.62 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added a 1Naqueous sodium hydroxide solution (2.4 mL) and the mixture was stirredat 50° C. for 2 hrs. 1N Hydrochloric acid and water were added toacidify the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated to give crystals (0.50 g,85%) of3-[2-ethoxy-4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionicacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 112-113° C.

Example 74

A mixture of[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methanol (1.20 g),thionyl chloride (0.6 mL), tetrahydrofuran (20 mL) and toluene (20 mL)was stirred at room temperature for 2 hrs. The precipitated crystalswere collected by filtration and washed with diisopropyl ether to givecrude crystals. A mixture of the obtained crystals, methyl2-(4-hydroxyphenyl)acetate (0.70 g), anhydrous potassium carbonate (0.92g) and N,N-dimethylformamide (20 mL) was stirred overnight at 80° C. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated. The obtained residue was subjectedto silica gel column chromatography to give methyl2-[4-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetateas a pale-yellow oil (1.52 g, 0.84%) from a fraction eluted with ethylacetate-hexane (1:1, v/v).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 3.57 (2H, s), 3.69 (3H, s), 5.06 (2H,s), 5.07 (2H, s), 6.86-6.98 (2H, m), 7.14-7.26 (2H, m), 7.40-7.54 (4H,m), 7.96-8.08 (2H, m), 8.30 (1H, d, J=1.4 Hz), 8.39 (1H, d, J=3.0 Hz).

Example 75

To a mixture of methyl2-[4-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetate(1.50 g), tetrahydrofuran (6 mL) and methanol (6 mL) was added a 1Naqueous sodium hydroxide solution (6 mL) and the mixture was stirred atroom temperature for 2 hrs. Dilute hydrochloric acid was added toacidify the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated to give crystals (1.36 g,94%) of2-[4-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]aceticacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 141-142° C.

Example 76

A mixture of2-[5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile(2.90 g), a 4N aqueous sodium hydroxide solution (15 mL) and ethanol (15mL) was heated under reflux for 4 hrs. Water was added to the reactionmixture, and the reaction mixture was neutralized with 1N hydrochloricacid and extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedto give crystals (2.58 g, 85%) of2-[5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid. Recrystallization from tetrahydrofuran-hexane gave colorless prismcrystals. melting point: 158-159° C.

Example 77

A mixture of [5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridyl]methanol(1.50), thionyl chloride (0.80 mL) and toluene (30 mL) was stirred atroom temperature for 2 hrs. The reaction mixture was concentrated andthe obtained crystals were collected by filtration using isopropylether. A mixture of the crystals, methyl 2-(3-hydroxyphenyl)acetate(0.70 g), anhydrous potassium carbonate (1.35 g) andN,N-dimethylformamide (20 mL) was stirred at 50° C. for 15 hrs. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and, concentrated. The obtained residue was subjectedto silica gel column chromatography to give methyl2-[3-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetateas a colorless oil (1.40 g, 75%) from a fraction eluted with ethylacetate-hexane (2:1, v/v).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 3.60 (2H, s), 3.69 (3H, s), 5.06 (2H,s), 5.08 (2H, s), 6.82-6.94 (3H, m), 7.18-7.32 (2H, m), 7.38-7.50 (4H,m), 7.96-8.08 (2H, m), 8.26-8.32 (1H, m), 8.36-8.42 (1H, m).

Example 78

To a mixture of methyl2-[3-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetate(1.35 g), tetrahydrofuran (6 mL) and methanol (6 mL) was added a 1Naqueous sodium hydroxide solution (6 mL) and the mixture was stirred atroom temperature for 3 hrs. The reaction mixture was concentrated, andwater and dilute hydrochloric acid were added to acidify the residue.The precipitated solid was collected by filtration to give crystals(1.25 g, 95%) of2-[3-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]aceticacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 143-144° C.

Example 79

To a mixture of 3-(5methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (0.859 g),methyl 2-(2-hydroxyphenyl)acetate (0.499 g), triphenylphosphine (0.944g) and tetrahydrofuran (15 mL) was dropwise added a solution (40%, 1.74g) of diethyl azodicarboxylate in toluene at room temperature, and themixture was stirred for 15 hrs. The reaction mixture was concentratedand the residue was subjected to silica gel column chromatography togive methyl2-[2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetateas an oil from a fraction eluted with ethyl acetate-hexane (1:2, v/v).This oil was dissolved in methanol-tetrahydrofuran (1:1, 20 mL) and a 1Naqueous sodium hydroxide solution (10 mL) was added. The mixture wasstirred at room temperature for 15 hrs. The reaction mixture was pouredinto water, 1N hydrochloric acid (10 mL) was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedto give crystals of2-[2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazoly]methoxylphenyl]aceticacid. Recrystallization from ethanol-hexane gave colorless needlecrystals (0.651 g, 52%). melting point: 152-153° C.

Example 80

A mixture of5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (457mg), methyl 2-(3-hydroxyphenyl)acetate (249 mg), anhydrous potassiumcarbonate (415 mg) and N,N-dimethylformamide (10 mL) was stirred at 60°C. for 3 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was subjected to silica gel column chromatography to give methyl2-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetateas a colorless oil (604 mg, 93%) from a fraction eluted with ethylacetate-hexane (1:1, v/v).

¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 3.60 (2H, s), 3.69 (3H, s), 5.04 (2H,s), 5.20 (2H, s), 6.01 (1H, s), 6.80-6.93 (3H, m), 7.25 (1H, t, J=8 Hz),7.40-7.47 (3H, m), 7.97-8.06 (2H, m).

Example 81

Methyl2-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetate(604 mg) was dissolved in methanol-tetrahydrofuran (1:1, 12 mL) and a 1Naqueous sodium hydroxide solution (3 mL) was added. The mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto water, 1N hydrochloric acid (3 mL) was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedto give crystals of2-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethloxy]phenyl]aceticacid. Recrystallization from ethanol-hexane gave colorless needlecrystals (522 mg, 89%). melting point: 128-129° C.

Example 82

To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(0.82 g), methyl 2-(2-hydroxy-5-propyl)phenylacetate (0.50 g) andN,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.12g) under ice-cooling, and the mixture was stirred at room temperaturefor 15 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed successively with waterand saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was subjected to silica gel columnchromatography to give methyl2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-propylphenyl]acetateas a colorless oil (0.70 g, 60%) from a fraction eluted with ethylacetate-hexane (1:5, v/v).

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.2 Hz), 1.51-1.67 (2H, m), 2.44 (3H,s), 2.51 (2H, t, J=7.6 Hz), 3.62 (3H, s), 3.63 (2H, s), 4.98 (2H, s),5.00 (2H, s), 6.84 (1H, d, J=8.0 Hz), 6.99-7.06 (4H, m), 7.31-7.36 (2H,d, J=8.8 Hz), 7.42-7.46 (3H, m), 7.99-8.05 (2H, m).

Example 83

To a mixture of methyl2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-propylphenyl]acetate(0.70 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1Naqueous sodium hydroxide solution (3 mL) and the mixture was stirred at50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidifythe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.60 g, 91%) of2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-propylphenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 116-117° C.

Example 84

To a mixture of[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]phenyl]methanol (0.50 g),methyl 2-(2-hydroxyphenyl)acetate (0.30 g), triphenylphosphine (0.60 g)and tetrahydrofuran (30 mL) was dropwise added a solution (40%, 1.00 g)of diethyl azodicarboxylate in toluene at room temperature, and themixture was stirred for 15 hrs. To the reaction mixture was added ethylacetate, and washed successively with water, a 2N aqueous sodiumhydroxide solution and saturated brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was subjected to silica gel columnchromatography to give methyl2-[2-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetateas an oil (0.40 g, 56%) from a fraction eluted with ethyl acetate-hexane(1:4, v/v).

¹H-NMR (CDCl₃) δ: 0.99 (3H, t, J=7.4 Hz), 1.63-1.80 (2H, m), 2.76 (2H,t, J=7.2 Hz), 3.62 (3H, s), 3.66 (2H, s), 5.00 (2H, s), 5.02 (2H, s),6.89-7.05 (4H, m), 7.18-7.48 (7H, m), 8.00-8.05 (2H, m).

Example 85

To a mixture of methyl2-[2-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.40 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1Naqueous sodium hydroxide solution (1.7 mL) and the mixture was stirredat 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidifythe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.30 g, 77%) of2-[2-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 129-130° C.

Example 86

To a mixture of[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]phenyl]methanol (0.50 g),methyl 2-(3-hydroxyphenyl)acetate (0.30 g), triphenylphosphine. (0.60 g)and tetrahydrofuran (30 mL) was dropwise added a solution (40%, 1.00 g)of diethyl azodicarboxylate in toluene at room temperature, and themixture was stirred for 15 hrs. To the reaction mixture was added ethylacetate, and the mixture was washed successively with water, a 2Naqueous sodium hydroxide solution and saturated brine. The mixture wasdried over anhydrous magnesium sulfate and concentrated. The residue wassubjected to silica gel column chromatography to give methyl2-[3-[[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetateas an oil (0.44 g, 62%) from a fraction eluted with ethyl acetate-hexane(1:4, v/v).

¹H-NMR (CDCl₃) δ: 0.99 (3H, t, J=7.2 Hz), 1.63-1.82 (2H, m), 2.57 (2H,t, J=7.4 Hz), 3.60 (2H, s), 3.69 (3H, s), 4.98 (2H, s), 5.00 (2H, s),6.85-6.91 (3H, m), 7.21-7.06 (2H, m), 7.20-7.48 (6H, m), 7.99-8.06 (2H,m).

Example 87

To a mixture of methyl2-[3-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate(0.44 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1Naqueous sodium hydroxide solution (2 mL) and the mixture was stirred at50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidifythe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.35 g, 81%) of2-[3-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 115-116° C.

Example 88

To a mixture of2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]acetonitrile(1.70 g) and ethanol (10 mL) was added a 2N aqueous sodium hydroxidesolution (10 mL) and the mixture was heated under reflux for 17 hrs. 1NHydrochloric acid (20 mL) and water were added to the reaction mixtureand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated to give crystals (1.60 g, 90%) of2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]aceticacid. Recrystallization from ethyl acetate gave colorless prismcrystals. melting point: 147-148° C.

Example 89

A mixture of4-chloromethyl-2-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]pyridine (457mg), methyl 3-hydroxyphenylacetate (249 mg), potassium carbonate (415mg) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 4 hrs.The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated. The residue was subjectedto silica gel column chromatography to give methyl3-[2-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-4-pyridyl]methoxy]phenylacetateas a colorless oil (524 mg, 80%) from a fraction eluted with ethylacetate-hexane (1:1, v/v).

¹H-NMR (CDCl₃) δ: 2.46 (3H, s), 3.59 (2H, br s), 3.68 (3H, s), 5.02 (2H,s), 5.29 (2H, s), 6.51 (1H, dd, J=3.6, 1.8 Hz), 6.79-6.96 (5H, m), 6.98(1H, dd, J=3.6, 0.8 Hz), 7.19-7.27 (1H, m), 7.53 (1H, dd, J=1.8, 0.6Hz), 8.15 (1H, dd, J=5.2, 0.6 Hz).

Example 90

To a solution of methyl3-[2-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-4-pyridyl]methoxy]phenylacetate(521 mg) in tetrahydrofuran-methanol (1:1, 12 mL) was dropwise added a1N aqueous sodium hydroxide solution (3 mL) at room temperature, and themixture was stirred for 1 hr. The reaction mixture was poured intowater, and the reaction mixture was neutralized with 1N hydrochloricacid (3 mL) and extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated to give crystals of3-[2-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-4-pyridyl]methoxy]phenylaceticacid. Recrystallization from ethanol-hexane gave colorless needlecrystals (473 mg, 94%). melting point: 136-137° C.

Example 91

A mixture of2-[2-[3-methoxy-4-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile(350 mg), ethanol (5 mL) and a 4N aqueous potassium hydroxide solution(5 mL) was heated under reflux for 4 hrs. Water was added to thereaction mixture, and the reaction mixture was neutralized with 2Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated to give crystals (236 mg, 65%) of2-[2-[3-methoxy-4-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid. The crystals were recrystallized from ethyl acetate-hexane to givecolorless prism crystals. melting point: 145-146° C.

Example 92

To a mixture of2-[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]-3-pyridyl]acetonitrile(0.60 g) and 2-methoxyethanol (2 mL) was added a 4N aqueous potassiumhydroxide solution (2 mL) and the mixture was heated under reflux for 4hrs. 1N Hydrochloric acid (8 mL) and water were added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated to give crystals (0.40 g, 63%) of2-[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]-3-pyridyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 151-152° C.

Example 93

To a mixture of2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile(0.94 g) and 2-methoxyethanol (8 mL) was added a 4N aqueous potassiumhydroxide solution (4 mL) and the mixture was heated under reflux for 5hrs. 1N Hydrochloric acid (16 mL) and water were added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was subjected to silicagel column chromatography to give crystals (0.58 g, 59%) of2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid from a fraction eluted with acetone-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 128-129° C.

Example 94

To a mixture of[4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]phenyl]methanol (0.50g), methyl 2-(2-hydroxyphenyl)acetate (0.27 g), triphenylphosphine (0.63g) and tetrahydrofuran (30 mL) was dropwise added a solution (40%, 1.04g) of diethyl azodicarboxylate in toluene at room temperature, and themixture was stirred for 15 hrs. To the reaction mixture was added ethylacetate, the mixture was washed successively with water, a 2N aqueoussodium hydroxide solution and saturated brine, dried over anhydrousmagnesium sulfate and concentrated. The residue was subjected to silicagel column chromatography to give methyl2-[2-[4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]benzyloxy]phenyl]acetateas a pale-yellow oil (0.4-6 g, 66%) from a fraction eluted with ethylacetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 3.65 (3H, s), 3.70 (2H, s), 5.09 (2H,s), 6.87-6.95 (3H, m), 7.20-7.53 (11H, m), 8.04-8.10 (1H, m).

Example 95

To a mixture of methyl2-[2-[4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]benzyloxy]phenyl]acetate(0.44 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1Naqueous sodium hydroxide solution (2 mL) and the mixture was stirred atroom temperature for 15 hrs. 1N Hydrochloric acid and water were addedto acidify the reaction mixture, and the, mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated to give crystals (0.31g, 72%) of2-[2-[4-[(E)-2-(5-methyl-2-phenyl-4-oxazolyl)ethenyl]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave pale-yellow prismcrystals. melting point: 189-190° C.

Example 96

To a mixture of[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]methanol (0.60 g),methyl 2-(2-hydroxyphenyl)acetate (0.35 g), triphenylphosphine (0.79 g)and tetrahydrofuran (50 mL) was dropwise added a solution (40%, 1.39 g)of diethyl azodicarboxylate in toluene at room temperature, and themixture was stirred for 15 hrs. To the reaction mixture was added ethylacetate, the mixture was washed successively with water, a 2N aqueoussodium hydroxide solution and saturated brine, dried over anhydrousmagnesium sulfate and concentrated. The residue was subjected to silicagel column chromatography to give methyl2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]benzyloxy]phenyl]acetateas a colorless oil (0.54 g, 58%) from a fraction eluted with ethylacetate-hexane (1:6, v/v).

¹H-NMR (CDCl₃) δ: 2.06 (3H, s), 2.73-2.81 (2H, m), 2.94-3.02 (2H, m),3.63 (3H, s), 3.68 (2H, s), 5.06 (2H, s), 6.89-6.97 (2H, m), 7.15-7.45(9H, m), 7.99-8.03 (2H, m).

Example 97

To a mixture of methyl2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]benzyloxy]phenyl]acetate(0.54 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added a 1Naqueous sodium hydroxide solution (3 mL) and the mixture was stirred atroom temperature for 15 hrs. 1N Hydrochloric acid and water were addedto acidify the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated to give crystals (0.40g, 78%) of2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]benzyloxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 130-131° C.

Example 98

To a mixture of4-[2-(4-chloromethyl-2-oxazolyl)ethyl]-5-methyl-2-phenyloxazole (0.50g), methyl 2-(2-hydroxyphenyl)acetate (0.25 g) and N,N-dimethylformamide(20 mL) was added sodium hydride (60%, oil, 0.07 g) under ice-cooling,and the mixture was stirred at room temperature for 15 hrs. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed successively with water, 2N aqueous sodiumhydroxide solution and saturated brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was subjected to silicagel column chromatography to give methyl2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetateas a colorless oil (0.43 g, 66%) from a fraction eluted with ethylacetate-hexane (1:2, v/v).

¹H-NMR (CDCl₃) δ: 2.27 (3H, s), 2.93-3.01 (2H, m), 3.11-3.20 (2H, m),3.66 (5H, s), 5.01 (2H, d, J=1.2 Hz), 6.91-6.99 (2H, m), 7.18-7.30 (2H,m), 7.40-7.46 (3H, m), 7.59 (1H, t, J=1.2 Hz), 7.94-8.00 (2H, m).

Example 99

To a mixture of methyl2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetate(0.44 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1Naqueous sodium hydroxide solution (2 mL) and the mixture was stirred at50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidifythe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.34 g, 81%) of2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 109-110° C.

Example 100

To a mixture of4-[2-(4-chloromethyl-2-oxazolyl)ethyl]-5-methyl-2-phenyloxazole (0.50g), methyl 2-(3-hydroxyphenyl)acetate (0.25 g) and N,N-dimethylformamide(20 mL) was added sodium hydride (60%, oil, 0.07 g) under ice-cooling,and the mixture was stirred at room temperature for 15 hrs. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed successively with water, 2N aqueous sodiumhydroxide solution and saturated brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was subjected to silicagel column chromatography to give, methyl2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetateas a colorless oil (0.35 g, 54%) from a fraction eluted with ethylacetate-hexane (1:2, v/v).

¹H-NMR (CDCl₃) δ: 2.27 (3H, s), 2.94-3.02 (2H, m), 3.12-3.21 (2H, m),3.60 (2H, s), 3.69 (3H, s), 4.97 (2H, s), 6.87-6.91 (3H, m), 7.20-7.28(1H, m), 7.39-7.46 (3H, m), 7.60 (1H, s), 7.94-8.60 (2H, m).

Example 101

To a mixture of methyl2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetate(0.34 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1Naqueous sodium hydroxide solution (2 mL) and the mixture was stirred at50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidifythe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.26 g, 79%) of2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 127-128° C.

Example 102

To a mixture of4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole (0.64g), methyl 2-(2-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide(20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling,and the mixture was stirred at room temperature for 15 hrs. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed successively with water, 2N aqueous sodiumhydroxide solution and saturated brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was subjected to silicagel column chromatography to give methyl2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetateas a colorless oil (0.49 g, 60%) from a fraction eluted with ethylacetate-hexane (1:3, v/v).

¹H-NMR (CDCl₃) δ: 2.22 (3H, s), 2.99 (2H, t, J=7.2 Hz), 3.40 (2H, t,J=7.2 Hz), 3.66 (3H, s), 3.71 (2H, s), 5.22 (2H, d, J=1.2 Hz), 6.90-6.99(2H, m), 7.19-7.30 (3H, m), 7.41-7.46 (3H, m), 7.96-8.01 (2H, m).

Example 103

To a mixture of methyl2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate(0.49 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1Naqueous sodium hydroxide solution (3 mL) and the mixture was stirred at50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated to give crystals (0.38 g, 79%) of2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 152-153° C.

Example 104

To a mixture of4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole (0.64g), methyl 2-(3-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide(20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling,and the mixture was stirred at room temperature for 15 hrs. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was washed successively with water, 2N aqueous sodiumhydroxide solution and saturated brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was subjected to silicagel column chromatography to give methyl2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetateas a colorless oil (0.31 g, 38%) from a fraction eluted with ethylacetate-hexane (1:3, v/v).

¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 2.99 (2H, t, J=7.4 Hz), 3.40 (2H, t,J=7.4 Hz), 3.60 (2H, s), 3.69 (3H, s), 5.16 (2H, s), 6.86-6.93 (3H, m),7.16-7.28 (2H, m), 7.38-7.46 (3H, m), 7.96-8.01 (2H, m).

Example 105

To a mixture of methyl2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate(0.31 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1Naqueous sodium hydroxide solution (3 mL) and the mixture was stirred at50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to thereaction mixture, and the precipitated crystals were collected byfiltration and air-dried to give crystals (0.23 g, 77%) of2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 153-154° C.

Example 106

To a mixture of5-chloromethyl-3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazole(0.61 g), methyl 2-(2-hydroxyphenyl)acetate (0.30 g) andN,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09g) under ice-cooling, and the mixture was stirred at room temperaturefor 15 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed successively withwater, 2N aqueous sodium hydroxide solution and saturated brine, driedover anhydrous magnesium sulfate and concentrated. The obtained residuewas subjected to silica gel column chromatography to give crystals (0.38g, 44%) methyl2-[2-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 109-110° C.

Example 107

To a mixture of methyl2-[2-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetate(0.30 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1Naqueous sodium hydroxide solution (3 mL) and the mixture was stirred at50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.22 g, 76%) of2-[2-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 120-121° C.

Example 108

To a mixture of5-chloromethyl-3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazole(0.61 g), methyl 2-(3-hydroxyphenyl)acetate (0.30 g) andN,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09g) under ice-cooling, and the mixture was stirred at room temperaturefor 15 hrs. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed successively withwater, 2N aqueous sodium hydroxide solution and saturated brine, driedover anhydrous magnesium sulfate and concentrated. The obtained residuewas subjected to silica gel column chromatography to give crystals (0.37g, 43%) of methyl2-[3-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).

Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 76-77° C.

Example 109

To a mixture of methyl2-[3-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetate(0.30 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1Naqueous sodium hydroxide solution (3 mL) and the mixture was stirred at50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to thereaction mixture, the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals (0.28 g, 97%) of2-[3-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 93-94° C.

Example 110

To a mixture of2-[6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile.(0.58 g), ethanol (10 mL) was added a 2N aqueous sodium hydroxidesolution (10 mL) and the mixture was heated under reflux for 24 hrs. 1NHydrochloric acid (20 mL) and water were added to the reaction mixtureand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated to give crystals (0.51 g, 82%) of2-[6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 138-139° C.

Example 111

To a mixture of[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]methanol (0.87 g),methyl 2-(2-oxo-1,2-dihydro-3-pyridyl)acetate (0.36 g),triphenylphosphine (0.87 g) and tetrahydrofuran (50 mL) was dropwiseadded a solution (40%, 1.47 g) of diethyl azodicarboxylate in toluene atroom temperature, and the mixture was stirred for 15 hrs. The reactionmixture was concentrated and the residue was subjected to silica gelcolumn chromatography to give an oil from a fraction eluted with ethylacetate-hexane (1:3, v/v). To a mixture of the obtained oil,tetrahydrofuran (3 mL) and methanol, (3 mL) was added an 1N aqueoussodium hydroxide solution (3 mL) and the mixture was stirred at roomtemperature for 2 hrs. 1N Hydrochloric acid (3 mL) and water were addedto the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated. The residue was subjectedto silica gel column chromatography to give crystals (0.14 g, 14%) of2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]-3-pyridyl]aceticacid from a fraction eluted with ethyl acetate-hexane (1:1, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 134-135° C.

Example 112

To a mixture of4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyl alcohol (0.69g), methyl 2-(2-hydroxyphenyl)acetate (0.40 g), triphenylphosphine (0.65g) and tetrahydrofuran (10 mL) was dropwise added a solution (40%, 1.18g) of diethyl azodicarboxylate in toluene at room temperature, and themixture was stirred overnight. The reaction mixture was concentrated andthe residue was subjected to silica gel column chromatography to give anoil from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Thisoil was dissolved in methanol-tetrahydrofuran (1:1, 10 mL), a 1N aqueoussodium hydroxide solution (5 mL) was added to the mixture, and themixture was stirred at room temperature for 4 hrs. Water was added tothe reaction mixture, and the mixture was neutralized with 1Nhydrochloric acid. The precipitated crystals (0.80 g, 80%) of2-[2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]phenyl]aceticacid were collected by filtration. Recrystallization from acetone-hexanegave colorless prism crystals. melting point: 160-161° C.

Example 113

To a mixture of3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolylmethanol (0.80 g),methyl 2-(2-hydroxyphenyl)acetate (0.45 g), tributylphosphine (1.05 g)and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine(1.31 g) at room temperature and the mixture was stirred for 3 days. Theprecipitated crystals were filtered off. The filtrate was concentratedand the residue was subjected to silica gel column chromatography togive crystals (0.55 g, 47%) of methyl2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 108-109° C.

Example 114

To a mixture of methyl2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]phenyl]acetate(0.44 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1Naqueous sodium hydroxide solution (3 mL) and the mixture was stirred at50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to thereaction mixture, and the precipitated crystals were collected byfiltration and dried with air to give crystals (0.40 g, 93%) of2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless needlecrystals. melting point: 147-148° C.

Example 115

To a mixture of2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrile(0.35 g) and ethanol (10 mL) was added a 2N aqueous sodium hydroxidesolution (10 mL) and the mixture was heated under reflux for 5 hrs. 1NHydrochloric acid (20 mL) and water were added to the reaction mixtureand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated to give crystals (0.30 g, 81%) of2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 109-110° C.

Example 116

To a mixture of[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-isoxazolyl]methanol (1.00g), methyl 2-(2-hydroxyphenyl)acetate (0.58 g), tributylphosphine (1.42g) and tetrahydrofuran (100 mL) was added1,1′-(azodicarbonyl)dipiperidine (1.77 g) at room temperature and themixture was stirred for 15 hrs. The precipitated crystals were filteredoff. The filtrate was concentrated and the residue was subjected tosilica gel column chromatography to give crystals (0.87 g, 59%) ofmethyl2-[2-[[3-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy]-5-isoxazolyl]methoxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 80-81° C.

Example 117

To a mixture of methyl2-[2-[[3-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy]-5-isoxazolyl]methoxy]phenyl]acetate(0.77 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1Naqueous sodium hydroxide solution (5 mL) and the mixture was stirred atroom temperature for 3 hrs. 1N Hydrochloric acid (5 mL) and water wereadded to the reaction mixture and the precipitated crystals werecollected by filtration and dried with air to give crystals (0.71 g,96%) of2-[2-[[3-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy]-5-isoxazolyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 159-160° C.

Example 118

To a mixture of[6-[2-[(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridyl]methanol (0.60g), methyl 2-(2-hydroxyphenyl)acetate (0.38 g), tributylphosphine (0.77g) and tetrahydrofuran (50 mL) was added1,1′-(azodicarbonyl)dipiperidine (0.96 g) at room temperature and themixture was stirred for 3 days. The precipitated crystals were filteredoff. The filtrate was concentrated and the residue was subjected tosilica gel column chromatography to give crystals (0.70 g, 80%) ofmethyl2-[2-[[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridyl]methoxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 78-79° C.

Example 119

To a mixture of methyl2-[2-[[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridyl]methoxy]phenyl]acetate(0.60 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1Naqueous sodium hydroxide solution (3 mL), and the mixture was stirred atroom temperature for 4 hrs. 1N Hydrochloric acid (3 mL) and water wereadded to the reaction mixture and the precipitated crystals werecollected by filtration and dried with air to give crystals (0.50 g,86%) of2-[2-[[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 159-160° C.

Example 120

To a mixture of5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethanol (1.00 g),methyl 2-(2-hydroxyphenyl)acetate (0.60 g), triphenylphosphine (0.96 g)and tetrahydrofuran (15 mL) was dropwise added a solution (40%, 1.68 g)of diethyl azodicarboxylate in toluene at room temperature, and themixture was stirred overnight. The reaction mixture was concentrated andthe residue was subjected to silica gel column chromatography to give anoil from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Thisoil was dissolved in methanol-tetrahydrofuran (1:1, 12 mL), and a 1Naqueous sodium hydroxide solution (6 mL) was added to the mixture. Themixture was stirred at room temperature for 3 hrs. Water was added tothe reaction mixture, and the mixture was neutralized with 1Nhydrochloric acid. The precipitated crystals (0.69 g, 47%) of2-[2-[[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-2-pyridyl]methoxy]phenyl]aceticacid were collected by filtration. Recrystallization from acetone-hexanegave colorless leaflet crystals. melting point: 180-181° C.

Example 121

To a mixture of[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methanol (1.00 g),methyl 2-(2-hydroxyphenyl)acetate (0.50 g), tributylphosphine (1.21 g)and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine(1.51 g) at room temperature and the mixture was stirred for 15 hrs. Theprecipitated crystals were filtered off. The filtrate was concentratedand the residue was subjected to silica gel column chromatography togive crystals (1.20 g, 87%) of methyl2-[2-[[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:6, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 119-120° C.

Example 122

To a mixture of methyl2-[2-[[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methoxy]-phenyl]acetate(1.05 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1Naqueous sodium hydroxide solution (5 mL) and the mixture was stirred at50° C. for 2 hrs. 1N Hydrochloric acid (5 mL) and water were added tothe reaction mixture, and the precipitated crystals were collected byfiltration and dried with air to give crystals (0.91 g, 88%) of2-[2-[[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 173-174° C.

Example 123

To a mixture of[6-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-pyridyl]methanol (1.36g), methyl 2-(2-hydroxyphenyl)acetate (0.45 g), tributylphosphine (1.09g) and tetrahydrofuran (100 mL) was added1,1′-(azodicarbonyl)dipiperidine (1.36 g) at room temperature and themixture was stirred for 15 hrs. The precipitated crystals were filteredoff and the filtrate was concentrated. The residue was subjected tosilica gel column chromatography to give crystals (0.83 g, 71%) ofmethyl2-[2-[[6-[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-pyridyl]methoxy]phenyl]acetatefrom a fraction eluted with ethyl acetate-hexane (1:2, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 84-85° C.

Example 124

To a mixture of methyl2-[2-[[6-[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-pyridyl]methoxy]phenyl]acetate(0.65 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1Naqueous sodium hydroxide solution (5 mL) and the mixture was stirred atroom temperature for 3 hrs. 1N Hydrochloric acid (5 mL) and water wereadded to the reaction mixture, and the precipitated crystals werecollected by filtration and dried with air to give crystals (0.60 g,95%) of2-[2-[[6-[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-pyridyl]methoxy]phenyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 119-120° C.

Example 125

To a mixture of2-[2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]acetonitrile(1.19 g) and ethanol (15 mL) was added a 2N aqueous sodium hydroxidesolution (15 mL) and the mixture was heated under reflux for 5 hrs. 1NHydrochloric acid (30 mL) and water were added to the reaction mixtureand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated to give crystals (1.08 g, 86%) of2-[2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]-3-pyridyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 126-127° C.

Example 126

To a mixture of2-[2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]-3-pyridyl]acetonitrile(0.30 g) and ethanol (15 mL) was added a 2N aqueous sodium hydroxidesolution (10 mL) and the mixture was heated under reflux for 24 hrs. 1NHydrochloric acid (20 mL) and water were added to the reaction mixture.The precipitated crystals were collected by filtration and dried withair to give crystals (0.23 g, 74%) of2-[2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]-3-pyridyl]aceticacid. Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 150-151° C.

Example 127

To a mixture of 4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzylalcohol (1.00 g), methyl 2-(4-hydroxyphenyl)acetate (643 mg),tributylphosphine (1.30 g) and tetrahydrofuran (30 mL) was added1,1′-(azodicarbonyl)dipiperidine (1.62 g) at room temperature and themixture was stirred for 16 hrs. The precipitated crystals were filteredoff. The filtrate was concentrated and the residue was subjected tosilica gel column chromatography to give methyl4-[4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyloxy]phenylacetate(1.48 g, quantitative) as a yellow oil from a fraction eluted with ethylacetate-hexane (1:4, v/v).

¹H-NMR (CDCl₃) δ: 3.08 (3H, s), 3.56 (2H, s), 3.68 (3H, s), 4.78 (2H,s), 5.03 (2H, s), 6.73 (1H, s), 6.92 (2H, d, J=8.4 Hz), 7.11-7.42 (9H,m), 7.85-7.89 (2H, m).

Example 128

A mixture of methyl4-[4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyloxy]phenylacetate(510 mg), a 1N aqueous sodium hydroxide solution (2.5 mL), methanol (5mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 1 hr. Waterwas added to the reaction mixture, 1N hydrochloric acid (3 mL) was addedto the mixture, and then the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated to give crystals of4-[4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyloxy]phenylaceticacid. The crystals were recrystallized from diethyl ether-hexane to givecolorless prism crystals (427 mg, 87%). melting point: 116-118° C.

Example 129

A mixture of2-[2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrile(1.02 g), a 2N aqueous sodium hydroxide solution (10 mL) and ethanol (20mL) was heated under reflux for 5 hrs. Water was added to the reactionmixture, and the mixture was neutralized with 2N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed with water,dried over anhydrous magnesium sulfate and concentrated to give crystals(820 mg, 77%) of2-[2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]aceticacid. Recrystallization from ethyl acetate-isopropyl ether gavecolorless needle crystals. melting point: 129-130° C.

Example 130

A mixture of2-[2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]-3-pyridyl]acetonitrile(700 mg), a 2N aqueous sodium hydroxide solution (20 mL) and ethanol (40mL) was heated under reflux for 18 hours. Water was added to thereaction mixture, and the mixture was neutralized with 2N hydrochloricacid and extracted with ethyl acetate. The organic layer was washed withwater, dried over anhydrous magnesium sulfate and concentrated. Theresidue was subjected to silica gel column chromatography to givecrystals (420 mg, 58%) of2-[2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]-3-pyridyl]aceticacid from a fraction eluted with acetone-hexane (2:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals. melting point: 155-156° C.

Example 131

A mixture of4-(5-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (400mg), methyl 3-hydroxyphenylacetate (195 mg), potassium carbonate (320mg) and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 2 hrs.The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and concentrated. The residue was subjected to silicagel column chromatography to give crystals of methyl3-[4-methoxy-3-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenylacetatefrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless prismcrystals (470 mg, 85%). melting point: 88-89° C.

Example 132

A mixture of methyl3-[4-methoxy-3-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenylacetate(420 mg), 1N sodium hydroxide (2 mL), methanol (5 mL) andtetrahydrofuran (5 mL) was stirred at room temperature for 3 hrs. Thereaction mixture was poured into water, and the mixture was neutralizedwith 2N hydrochloric acid to give crystals of3-[4-methoxy-3-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenylaceticacid. Recrystallization from ethyl acetate gave colorless prism crystals(350 mg, 86%). melting point: 114-115° C.

Example 133

To a mixture of2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarbaldehyde(2.00 g), triethyl phosphonoacetate (1.17 g) and N,N-dimethylformamide(15 ml) was added sodium hydride (0.19 g) at room temperature and themixture was stirred for 3 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography to give ethyl3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]propenoateas a colorless oil (2.19 g, yield 93%) from a fraction eluted with ethylacetate-hexane (1:4, v/v).

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.0 Hz), 2.44 (3H, s), 4.25 (2H, q,J=7.0 Hz), 5.01 (2H, s), 5.44 (2H, s), 6.59 (1H, d, J=16.2 Hz), 6.93(1H, dd, J=7.8, 5.0 Hz), 6.98-7.08 (2H, m), 7.36-7.52 (5H, m), 7.76 (1H,dd, J=7.8, 1.8 Hz), 7.84 (1H, d, J=16.2 Hz), 7.96-8.08 (2H, m), 8.18(1H, dd, J=5.0, 1.8 Hz).

Example 134

To a mixture of ethyl3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]propenoate(2.00 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added a 1Naqueous sodium hydroxide solution (7 mL) and the mixture was stirred at70° C. for 3 hrs. The reaction mixture was concentrated, and dilutehydrochloric acid was added to acidify the residue. The precipitatedsolid was collected by filtration and dried with air to give crystals(1.77 g, yield 94%) of3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]propenoicacid. Recrystallization from tetrahydrofuran-diisopropyl ether gavecolorless prism crystals. melting point: 174-175° C.

Example 135

To a mixture of2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]-3-pyridinecarbaldehyde(0.30 g), triethyl phosphonoacetate. (0.18 g) and N,N-dimethylformamide(15 ml) was added sodium hydride (0.04 g) at room temperature and themixture was stirred for 15 hrs. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated to give crystals (0.28 g, yield 80%) of ethyl3-[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]-3-pyridyl]propenoate. Recrystallization from ethylacetate-hexane gave colorless prism crystals. melting point: 85-87° C.

Example 136

2-[2-[4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid (0.20 g) was added to a mixture of lithium hydroxide monohydrate(19 mg), methanol (5 mL) and tetrahydrofuran (5 mL) at room temperature,and the mixture was stirred for 30 min. The reaction mixture wasconcentrated, and the residue was crystallized from methanol and diethylether to give crystals (0.18 g, yield 90%) of lithium2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetate.Recrystallization from methanol-diethyl ether gave colorless prismcrystals. melting point: 207-209° C.

Example 137

2-[2-[4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid (0.30 g) was added to a mixture of a 1N aqueous sodium hydroxidesolution (0.7 mL), methanol (5 mL) and tetrahydrofuran (5 mL) at roomtemperature, and the mixture was stirred for 1 hr. The reaction mixturewas concentrated and water (5 mL) was added to the residue. Further, anaqueous solution (3 mL) of calcium chloride (78 mg) was added at roomtemperature. The precipitated crystals were collected by filtration,washed with water to give crystals (0.24 g, yield 77%) of calcium2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetatedihydrate. Recrystallization from tetrahydrofuran-hexane gave colorlessprism crystals. melting point: 140-145° C.

Example 138

2-[2-[4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid (0.20 g) was added to a mixture of a 1N aqueous potassium hydroxidesolution (0.46 mL), methanol (5 mL) and tetrahydrofuran (5 mL) at 0° C.,and the mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated, and the residue was washed with diethyl etherto give crystals (0.19 g, yield 86%) of potassium2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetate.Recrystallization from methanol-diethyl ether gave colorless prismcrystals. melting point: 157-159° C.

Example 139

A mixture of2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetonitrile(1.03 g), a 4N aqueous potassium hydroxide solution (30 mL),tetrahydrofuran (10 mL) and ethanol (30 mL) was stirred with heatingunder reflux for 14 hrs. The reaction mixture was concentrated and waterwas added to the residue. The mixture was acidified with 2N hydrochloricacid and extracted with ethyl acetate. The organic layer was washed withwater, dried over anhydrous magnesium sulfate and concentrated. Theresidue was subjected to silica gel column chromatography to givecrystals (0.87 g, yield 81%) of2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]aceticacid from a fraction eluted with ethyl acetate-methanol (50:1, v/v).Recrystallization from acetone-hexane gave colorless needle crystals.melting point: 81-82° C.

Example 140

A mixture of diethyl2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzyl]malonate(0.70 g), a 4N aqueous potassium hydroxide solution (10 mL),tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred at 60° C. for 1hr. The reaction mixture was concentrated and water was added to theresidue. The mixture was neutralized with 2N hydrochloric acid, and theprecipitated crystals were collected by filtration. The obtainedcrystals were dissolved in pyridine (40 mL) and this mixture was stirredwith heating under reflux for 1 hr. The reaction mixture wasconcentrated, 2N hydrochloric acid was added to the mixture and themixture was extracted with ethyl acetate. The organic layer was washedwith water, dried over anhydrous magnesium sulfate and concentrated togive crystals (0.44 g, yield 77%) of3-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]propionicacid. Recrystallization from acetone-hexane gave colorless prismcrystals. melting point: 120-121° C.

Example 141

A mixture of methyl[3-chloro-4-[(dimethylamino)carbonylthio]phenyl]acetate (0.80 g), a 28%solution of sodium methoxide in methanol (0.75 g) and methanol (20 mL)was stirred with heating under reflux for 2 hrs.4-(3-Chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.87 g) wasadded to the reaction mixture at room temperature and the mixture wasfurther stirred for 12 hrs. The reaction mixture was poured into 0.1Nhydrochloric acid and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water, dried over anhydrous magnesiumsulfate and concentrated. The residue was subjected to silica gel columnchromatography to give methyl2-[3-chloro-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetateas a colorless oil (0.48 g, yield 35%), from a fraction eluted withethyl acetate-hexane (1:3, v/v).

¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 3.55 (2H, s), 3.69 (3H, s), 4.12 (2H,s), 4.96 (2H, s), 6.88-7.08 (4H, m), 7.16-7.31 (3H, m), 7.41-7.47 (3H,m), 7.99-8.04 (2H, m).

Example 142

A mixture of methyl2-[3-chloro-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetate.(0.47 g), a 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran(5 mL) and methanol (5 mL) was stirred at room temperature for 1 hr. Thereaction mixture was poured into water and acidified with 1Nhydrochloric acid. The precipitated solid was collected by filtrationand dried with air to give crystals (0.43 g, yield 94%) of2-[3-chloro-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]aceticacid. Recrystallization from ethyl acetate-methanol gave colorless prismcrystals. melting point: 150-151° C.

Example 143

Triethylamine (0.195 g) was added to a mixture of4-(5-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (0.30g), 3-(4-mercaptophenyl)propionic acid (0.16 g) andN,N-dimethylformamide (10 mL) with stirring at room temperature and themixture was further stirred for 2 hrs. The reaction mixture was pouredinto water and acidified with 2N hydrochloric acid. The precipitatedcrystals were collected by filtration and the obtained crystals weresubjected to silica gel column chromatography to give crystals (0.21 g,yield 49%) of3-[4-[3-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]propionicacid from a fraction eluted with acetone-hexane (1:1, v/v).Recrystallization from acetone-diisopropyl ether gave colorless prismcrystals. melting point: 181-182° C.

Example 144

Triethylamine (0.305 g) was added to a mixture of4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.43 g),3-(4-mercaptophenyl)propionic acid (0.25 g) and N,N-dimethylformamide(10 mL) with stirring at room temperature, and the mixture was furtherstirred for 2 hrs. The reaction mixture was poured into water, acidifiedwith 2N hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with water, dried over anhydrous magnesium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography to give crystals (0.37 g, yield 59%) of3-[4-[3-[3-(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]propionicacid from a fraction eluted with acetone-hexane (1:1, v/v).Recrystallization from acetone-diisopropyl ether gave colorless prismcrystals. melting point: 128-129° C.

Example 145

Sodium t-butoxide (2.86 g) was added to dimethyl sulfoxide (20 ml), andafter stirring at room temperature for 50 min., tetrahydrofuran (30 ml)was added and ice-cooled. Trimethylsulfonium iodide (4.04 g) was addedto the mixture, and after stirring under ice-cooling for 10 min., asolution of sodiumhydroxy[2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)pyridin-3-yl]methanesulfonate(5 g) in dimethyl sulfoxide (15 ml) was dropwise added under ice-coolingand the mixture was stirred under ice-cooling for 1 hr. and at roomtemperature for 1 hr. The reaction solution was poured into iced water(100 ml) and extracted twice with t-butylmethyl ether (50 ml). Theorganic layers were combined, washed 4 times with water (50 ml) andconcentrated under reduced pressure to give2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)-3-oxiran-2-ylpyridine.

The compound was dissolved in tetrahydrofuran (37 ml) under an argonstream and after cooling to −10° C., a 1.5 M solution (7.1 ml) ofdiisobutylaluminum hydride in toluene was dropwise added at −5° C.-−10°C. The reaction solution was stirred at the same temperature for 40min., and a 20% Rochelle salt solution (37 ml) was dropwise added whilemaintaining the mixture at not higher than 5° C. The temperature of thereaction solution was elevated to 20-30° C. and t-butylmethyl ether (74ml) was added. The organic layer was separated and washed with 20%Rochelle salt and water and dried over anhydrous sodium sulfate. Theorganic layer was concentrated under reduced pressure, t-Butylmethylether (4.5 ml) was added to the residue and the mixture was stirred atroom temperature for 50 min. and n-heptane (2 ml) was added. The mixturewas stirred at room temperature for 55 min., and the precipitatedcrystals were collected by filtration, washed with t-butylmethylether/n-heptane=2/1 (5 ml) ice-cooled in advance and dried under reducedpressure to give2-[2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)pyridin-3-yl]ethanolas white crystals.

¹H-NMR (CDCl₃, δ, 300 MHz); 1.91 (1H, t, J=5.4 Hz), 2.50 (3H, s), 2.93(2H, t, J=6.4 Hz), 3.90 (2H, m), 5.06 (2H, s), 5.41 (2H, s), 7.70 (2H,d, J=8.6 Hz), 7.32-7.53 (6H, m), 8.06-8.13 (3H, m).

Example 146

Sodium dihydrogenphosphate dihydrate (10.45 g) was dissolved in water(80 ml) and the mixture was adjusted to pH=6.70 with 6N-sodiumhydroxide. Water (13 ml) was added to give a phosphate buffer.

2-[2-({4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)pyridin-3-yl]ethanol(10.0 g) was suspended in acetonitrile (100 ml) and the aforementionedphosphate buffer (70 ml) and 2,2,6,6-tetramethyl-1-piperidinyloxyradical(131.2 mg) was added at 25° C. To the obtained mixture weresimultaneously added dropwise a solution of 5% sodium hypochlorite (355mg) in water (5 ml) and a solution of sodium chlorite (5.43 g) in water(15 ml) at 25° C. and the mixture was stirred for 1 hr. 0.2N-Sodiumhydroxide was added to adjust the reaction solution to pH 8, and asolution of sodium sulfite (7.260 g) in water (100 ml) was dropwiseadded. The reaction solution was stirred for 20 min. and acetonitrilewas evaporated under reduced pressure. Toluene (100 ml), tetrahydrofuran(50 ml) and 2N-sodium hydroxide (12 ml) were added to the residue topartition the mixture. The organic layer was extracted with water (50ml), and aqueous layers were combined and washed with a mixture oftoluene (100 ml) and tetrahydrofuran (50 ml). 6N Hydrochloric acid wasdropwise added to adjust the aqueous layer to pH 7.0, and toluene (150ml) and tetrahydrofuran (70 ml) were added 6N Hydrochloric acid wasadded to adjust the mixture to pH 6.5 and the mixture was partitioned.The organic layer was washed with 5% brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. Tetrahydrofuran (20 ml)was added to the obtained crystals and the mixture was refluxed.Isopropyl ether (20 ml) was added to the obtained solution, and afterstirring for 1 hr., the mixture was stirred under ice-cooling for 2 hrs.The obtained crystals were filtrated, washed with isopropyl ether (20ml) ice-cooled in advance, and dried under reduced pressure at 40° C. togive2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid as white crystals.

¹H-NMR (CDCl₃, δ, 300 MHz); 2.40 (3H, s), 3.63 (2H, s), 4.95 (2H, s),5.31 (2H, s), 6.84-6.87 (1H, m), 6.93 (2H, d, J=8.7 Hz), 7.32-7.50 (6H,m), 8.00-8.15 (3H, m).

Example 147

1N Sodium hydroxide-methanol solution (2.4 ml) was added to2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid (1.0 g) and the mixture was heated to 40° C. The obtained solutionwas allowed to cool and acetone (10 ml) was added. The mixture wasstirred at room temperature for 30 min and acetone (5 ml) was furtheradded. The mixture was stirred at room temperature for 1 hr, and underice-cooling for 1 hr. The precipitated crystals were collected byfiltration, washed with acetone (10 ml) ice-cooled in advance, and driedunder reduced pressure to give sodium2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetateas white crystals.

¹H-NMR (DMSO-d₆, δ, 300 MHz); 2.43 (3H, s), 3.20 (2H, s), 4.98 (2H, s),5.25 (2H, s), 6.83-6.87 (1H, m), 7.01 (2H, d, J=8.6 Hz), 7.39 (2H, d,J=8.6 Hz), 7.50-7.54 (4H, m), 7.90-7.96 (3H, m).

Preparation Example 1 Production of Capsules

1) Compound of Example 4 30 mg 2) Cellulose (fine powder) 10 mg 3)Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg

1), 2), 3) and 4) are admixed and filled into a gelatin capsule.

Preparation Example 2 Production of Tablets

1) Compound of Example 4 30 g 2) Lactose 50 g 3) Corn starch 15 g 4)Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g 1000tablets total 140 g

The whole amounts of 1), 2) and 3) and 30 g of 4) are kneaded togetherwith water and the mixture, after drying in vacuo, is granulated. Thegranular mixture is admixed with 14 g of 4) and 1 g of 5) and theresulting mixture is tableted using a tableting machine to give 1000tablets each containing 30 mg of compound of Example 4.

INDUSTRIAL APPLICABILITY

The compound of the present invention is of low toxicity and can be usedas, for example, a prophylactic or therapeutic agent of diabetesmellitus (e.g. type 1 diabetes mellitus, type 2 diabetes mellitus,gestational diabetes mellitus, etc.); a prophylactic or therapeuticagent of hyperlipidemia (e.g., hypertriglyceridemia,hypercholesterolemia, hypo-high-density lipoproteinemia, postprandialhyperlipemia etc.); an insulin sensitivity enhancing agent; aretinoid-related receptor function regulating agent; an insulinsensitizer; a prophylactic or therapeutic agent of impaired glucosetolerance (IGT); and an agent for preventing progress from impairedglucose tolerance to diabetes mellitus.

The compound of the present can be used also as, for example, aprophylactic or therapeutic agent of diabetic complications (e.g.,neuropathy, nephropathy, retinopathy, cataract, macroangiopathy,osteopenia, diabetic hyperosmolar coma, infectious diseases (e.g.,respiratory infection, urinary tract infection, gastrointestinal tractinfection, dermal soft tissue infection, inferior limb infection, etc.),diabetic gangrene, xerostomia, lowered sense of hearing, cerebrovasculardisease, peripheral circulatory disturbance, etc.), obesity,osteoporosis, cachexia (e.g., carcinomatous cachexia, tuberculouscachexia, diabetic cachexia, hemopathic cachexia, endocrinopathiccachexia, infectious cachexia, cachexia induced by acquiredimmunodeficiency syndrome), fatty liver, hypertension, polycystic ovarysyndrome, renal diseases (e.g., diabetic nephropathy, glomerularnephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis, terminal renal disease etc.), muscular dystrophy,myocardiac infarction, angina pectoris, cerebrovascular disease (e.g.,cerebral infarction, cerebral apoplexy), insulin resistant syndrome,syndrome X, hyperinsulinemia, hyperinsulinemia-induced sensory disorder,tumor (e.g., leukemia, breast cancer, prostate cancer, skin cancer,etc.), irritable intestinal syndrome, acute or chronic diarrhea,inflammatory diseases (e.g., chronic rheumatoid arthritis, spondylitisdeformans, osteoarthritis, lumbago, gout, postoperative or traumaticinflammation, remission of swelling, neuralgia, pharyngolaryngitis,cystitis, hepatitis (including non-alcoholic steatohepatitis),pneumonia, pancreatitis, inflammatory colonic disease, ulcerativecolitis, etc.), visceral obesity syndrome, arteriosclerosis (e.g.,atherosclerosis, etc.), etc.

Also, the compound of the present invention can be used for amelioratingconditions such as bellyache, nausea, vomiting, or dysphoria inepigastrium and the like, each of which is accompanied bygastrointestinal ulcer, acute or chronic gastritis, biliary dyskinesia,cholecystitis, etc., and the like.

Further, the compound of the present invention can control (enhance orinhibit) appetite and food intake, and therefore, can be used as anagent for treating, for example, leanness and cibophobia (the weightincrease in administration, subjects suffering from leanness orcibophobia) or an agent for treating obesity.

According to the present invention, moreover, a production method of thecompound of the present invention can be provided.

This application is based on patent application No. 2000-402648 filed inJapan, the contents of which are all hereby incorporated by reference.

1. A compound represented by the formula

wherein R¹ is an oxazolyl group which may have 1 to 4 substituentsselected from the group consisting of (1) halogen atom, (2) nitro group,(3) an aliphatic hydrocarbon group having 1 to 15 carbon atoms, (4) analicyclic hydrocarbon group having 3 to 12 carbon atoms, (5) an aromatichydrocarbon group having 6 to 14 carbon atoms, (6) an acyl group whichmay have 1 to 3 substituents selected from the group consisting of aC₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms, a C₁₋₆alkoxy group optionally substituted by 1 to 3 halogen atoms, a halogenatom, nitro, hydroxy, and amino, (7) an amino group optionally mono- ordi-substituted by alkyl group having 1 to 10 carbon atoms, alkenyl grouphaving 2 to 10 carbon atoms, cycloalkyl group having 3 to 10 carbonatoms, cycloalkenyl group having 3 to 10 carbon atoms, aryl group having6 to 14 carbon atoms or acyl group having 1 to 13 carbon atoms, (8) ahydroxy group which is optionally substituted by alkyl group having 1 to10 carbon atoms, alkenyl group having 2 to 10 carbon atoms, aralkylgroup having 7 to 13 carbon atoms, acyl group having 1 to 13 carbonatoms or aryl group having 6 to 14 carbon atoms, each of which group mayhave 1 or 2 substituents selected from the group consisting of a halogenatom and an alkoxy group having 1 to 3 carbon atoms, and (9) a thiolgroup which is optionally substituted by alkyl group having 1 to 10carbon atoms, cycloalkyl group having 3 to 10 carbon atoms, aralkylgroup having 7 to 13 carbon atoms, acyl group having 2 to 13 carbonatoms or aryl group having 6 to 14 carbon atoms, wherein the above (3)may have 1 to 3 substituents selected from the group consisting of 1) acycloalkyl group having 3 to 10 carbon atoms, 2) an aryl group having 6to 14 carbon atoms, 3) an aralkyl group having 7 to 9 carbon atoms, 4)an amino group, 5) an amino group mono- or di-substituted by alkyl grouphaving 1 to 4 carbon atoms or acyl group having 2 to 8 carbon atoms, 6)an amidino group, 7) an acyl group having 2 to 8 carbon atoms, 8) acarbamoyl group, 9) a carbamoyl group mono- or di-substituted by alkylgroup having 1 to 4 carbon atoms, 10) a sulfamoyl group, 11) a sulfamoylgroup mono- or di-substituted by alkyl group having 1 to 4 carbon atoms,12) a carboxyl group, 13) an alkoxycarbonyl group having 2 to 8 carbonatoms, 14) a hydroxy group, 15) a C₁₋₆ alkoxy group optionallysubstituted by 1 to 3 halogen atoms, 16) a C₂₋₅ alkenyloxy groupoptionally substituted by 1 to 3 halogen atoms, 17) a cycloalkyloxygroup having 3 to 7 carbon atoms, 18) an aralkyloxy group having 7 to 9carbon atoms, 19) an aryloxy group having 6 to 14 carbon atoms, 20) athiol group, 21) a C₁₋₆ alkylthio group optionally substituted by 1 to 3carbon atoms, 22) an aralkylthio group having 7 to 9 carbon atoms, 23)an arylthio group having 6 to 14 carbon atoms, 24) a sulfo group, 25) acyano group, 26) an azide group, 27) a nitro group, 28) a nitroso group,and 29) a halogen atom, wherein the above (4) and (5) may have 1 to 3substituents selected from the group consisting of 1) a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 halogen atoms, 2) a C₂₋₆ alkenyl groupoptionally substituted by 1 to 3 halogen atoms, 3) a cycloalkyl grouphaving 3 to 10 carbon atoms, 4) an aromatic hydrocarbon group having 6to 14 carbon atoms, 5) an aralkyl group having 7 to 9 carbon atoms, 6)an amino group, (7) an amino group mono- or di-substituted by alkylgroup having 1 to 4 carbon atoms or acyl group having 2 to 8 carbonatoms, 8) an amidino group, 9) an acyl group having 2 to 8 carbon atoms,10) a carbamoyl group, 11) a carbamoyl group mono- or di-substituted byalkyl group having 1 to 4 carbon atoms, 12) a sulfamoyl group, 13) asulfamoyl group mono- or di-substituted by alkyl group having 1 to 4carbon atoms, 14) a carboxyl group, 15) an alkoxycarbonyl group having 2to 8 carbon atoms, 16) a hydroxy group, 17) a C₁₋₆ alkoxy groupoptionally substituted by 1 to 3 halogen atoms, 18) a C₂₋₅ alkenyloxygroup optionally substituted by 1 to 3 halogen atoms, 19) acycloalkyloxy group having 3 to 7 carbon atoms, 20) an aralkyloxy grouphaving 7 to 9 carbon atoms, 21) an aryloxy group having 6 to 14 carbonatoms, 22) a thiol group, 23) a C₁₋₆ alkylthio group optionallysubstituted by 1 to 3 halogen atoms, 24) an aralkylthio group having 7to 9 carbon atoms, 25) an arylthio group having 6 to 14 carbon atoms,26) a sulfo group, 27) a cyano group, 28) an azide group, 29) a nitrogroup, 30) a nitroso group, and 31) a halogen atom; X is a bond; Q is analkylene group having 1 to 20 carbon atoms; Y is an oxygen atom; ring Ais a benzene ring optionally further having 1 to 3 substituents selectedfrom the group consisting of (1) an aliphatic hydrocarbon group having 1to 15 carbon atoms which may have 1 to 3 substituents selected from thegroup consisting of 1) a cycloalkyl group having 3 to 10 carbon atoms,2) an aryl group having 6 to 14 carbon atoms, 3) an aralkyl group having7 to 9 carbon atoms, 4) an amino group, 5) an amino group mono- ordi-substituted by alkyl group having 1 to 4 carbon atoms or acyl grouphaving 2 to 8 carbon atoms, 6) an amidino group, 7) an acyl group having2 to 8 carbon atoms, 8) a carbamoyl group, 9) a carbamoyl group mono- ordi-substituted by alkyl group having 1 to 4 carbon atoms, 10) asulfamoyl group, 11) a sulfamoyl group mono- or di-substituted by alkylgroup having 1 to 4 carbon atoms, 12) a carboxyl group, 13) analkoxycarbonyl group having 2 to 8 carbon atoms, 14) a hydroxy group,15) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen atoms,16) a C₂₋₅ alkenyloxy group optionally substituted by 1 to 3 halogenatoms, 17) a cycloalkyloxy group having 3 to 7 carbon atoms, 18) anaralkyloxy group having 7 to 9 carbon atoms, 19) an aryloxy group having6 to 14 carbon atoms, 20) a thiol group, 21) a C₁₋₆ alkylthio groupoptionally substituted by 1 to 3 carbon atoms, 22) an aralkylthio grouphaving 7 to 9 carbon atoms, 23) an arylthio group having 6 to 14 carbonatoms, 24) a sulfo group, 25) a cyano group, 26) an azide group, 27) anitro group, 28) a nitroso group, and 29) a halogen atom, (2) a hydroxygroup which is optionally substituted by alkyl group having 1 to 10carbon atoms, alkenyl group having 2 to 10 carbon atoms, aralkyl grouphaving 7 to 13 carbon atoms, acyl group having 1 to 13 carbon atoms oraryl group having 6 to 14 carbon atoms, each of which group may have 1to 2 substituents selected from the group consisting of a halogen atomand an alkoxy group having 1 to 3 carbon atoms, (3) halogen atom, (4) anacyl group which may have 1 to 3 substituents selected from the groupconsisting of a C₁₋₆ alkyl group optionally substituted by 1 to 3halogen atoms, a C₁₋₆ alkoxy group optionally substituted by 1 to 3halogen atoms, a halogen atom, nitro, hydroxy, and amino, (5) nitrogroup, and (6) an amino group optionally mono- or di-substituted byalkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10carbon atoms, cycloalkyl group having 3 to 10 carbon atoms, cycloalkenylgroup having 3 to 10 carbon atoms, aryl group having 6 to 14 carbonatoms or acyl group having 1 to 13 carbon atoms; Z is —(CH₂)_(n)—O— (nis an integer of 1 to 8); ring B is a pyridine ring which optionallyfurther has 1 to 3 substituents selected from the group consisting of(1) an aliphatic hydrocarbon group having 1 to 15 carbon atoms which mayhave 1 to 3 substituents selected from the group consisting of 1) acycloalkyl group having 3 to 10 carbon atoms, 2) an aryl group having 6to 14 carbon atoms, 3) an aralkyl group having 7 to 9 carbon atoms, 4)an amino group, 5) an amino group mono- or di-substituted by alkyl grouphaving 1 to 4 carbon atoms or acyl group having 2 to 8 carbon atoms, 6)an amidino group, 7) an acyl group having 2 to 8 carbon atoms, 8) acarbamoyl group, 9) a carbamoyl group mono- or di-substituted by alkylgroup having 1 to 4 carbon atoms, 10) a sulfamoyl group, 11) a sulfamoylgroup mono- or di-substituted by alkyl group having 1 to 4 carbon atoms,12) a carboxyl group, 13) an alkoxycarbonyl group having 2 to 8 carbonatoms, 14) a hydroxy group, 15) a C₁₋₆ alkoxy group optionallysubstituted by 1 to 3 halogen atoms, 16) a C₂₋₅ alkenyloxy groupoptionally substituted by 1 to 3 halogen atoms, 17) a cycloalkyloxygroup having 3 to 7 carbon atoms, 18) an aralkyloxy group having 7 to 9carbon atoms, 19) an aryloxy group having 6 to 14 carbon atoms, 20) athiol group, 21) a C₁₋₆ alkylthio group optionally substituted by 1 to 3carbon atoms, 22) an aralkylthio group having 7 to 9 carbon atoms, 23)an arylthio group having 6 to 14 carbon atoms, 24) a sulfo group, 25) acyano group, 26) an azide group, 27) a nitro group, 28) a nitroso group,and 29) a halogen atom, (2) an aromatic hydrocarbon group having 6 to 14carbon atoms which may have 1 to 3 substituents selected from the groupconsisting of 1) a C₁₋₆ alkyl group optionally substituted by 1 to 3halogen atoms, 2) a C₂₋₆ alkenyl group optionally substituted by 1 to 3halogen atoms, 3) a cycloalkyl group having 3 to 10 carbon atoms, 4) anaromatic hydrocarbon group having 6 to 14 carbon atoms, 5) an aralkylgroup having 7 to 9 carbon atoms, 6) an amino group, (7) an amino groupmono- or di-substituted by alkyl group having 1 to 4 carbon atoms oracyl group having 2 to 8 carbon atoms, 8) an amidino group, 9) an acylgroup having 2 to 8 carbon atoms, 10) a carbamoyl group, 11) a carbamoylgroup mono- or di-substituted by alkyl group having 1 to 4 carbon atoms,12) a sulfamoyl group, 13) a sulfamoyl group mono- or di-substituted byalkyl group having 1 to 4 carbon atoms, 14) a carboxyl group, 15) analkoxycarbonyl group having 2 to 8 carbon atoms, 16) a hydroxy group,17) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen atoms,18) a C₂₋₅ alkenyloxy group optionally substituted by 1 to 3 halogenatoms, 19) a cycloalkyloxy group having 3 to 7 carbon atoms, 20) anaralkyloxy group having 7 to 9 carbon atoms, 21) an aryloxy group having6 to 14 carbon atoms, 22) a thiol group, 23) a C₁₋₆ alkylthio groupoptionally substituted by 1 to 3 halogen atoms, 24) an aralkylthio grouphaving 7 to 9 carbon atoms, 25) an arylthio group having 6 to 14 carbonatoms, 26) a sulfo group, 27) a cyano group, 28) an azide group, 29) anitro group, 30) a nitroso group, and 31) a halogen atom, (3) a hydroxygroup which is optionally substituted by alkyl group having 1 to 10carbon atoms, alkenyl group having 2 to 10 carbon atoms, aralkyl grouphaving 7 to 13 carbon atoms, acyl group having 1 to 13 carbon atoms oraryl group having 6 to 14 carbon atoms, each of which group may have 1to 2 substituents selected from the group consisting of a halogen atomand an alkoxy group having 1 to 3 carbon atoms, (4) halogen atom, (5) anacyl group which may have 1 to 3 substituents selected from the groupconsisting of a C₁₋₆ alkyl group optionally substituted by 1 to 3halogen atoms, a C₁₋₆ alkoxy group optionally substituted by 1 to 3halogen atoms, a halogen atom, nitro, hydroxy, and amino, (6) nitrogroup, and (7) an amino group optionally mono- or di-substituted byalkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10carbon atoms, cycloalkyl group having 3 to 10 carbon atoms, cycloalkenylgroup having 3 to 10 carbon atoms, aryl group having 6 to 14 carbonatoms or acyl group having 1 to 13 carbon atoms; U is a bond; W is analkylene group having 1 to 20 carbon atoms; and R³ is —OR⁸ (R⁸ is ahydrogen atom, alkyl group having 1 to 4 carbon atoms, or C₆₋₁₀ arylgroup optionally having 1 to 3 substituents selected from alkyl grouphaving 1 to 4 carbon atoms and halogen atom); or a salt thereof.
 2. Thecompound of claim 1, wherein Q is C₁₋₆ alkylene.
 3. The compound ofclaim 1, wherein n is an integer of 1 to
 3. 4. The compound of claim 1,wherein W is a C₁₋₆ alkylene.
 5. The compound of claim 1, wherein R¹ isan oxazolyl group which optionally has 1 to 3 substituents selectedfrom 1) a C₁₋₁₀ alkyl group optionally having 1 to 3 substituentsselected from a C₁₋₆ alkoxy group optionally substituted by 1 to 3halogen atoms, a halogen atom, a nitro group, a hydroxy group and anamino group; 2) a C₃₋₁₀ cycloalkyl group optionally having 1 to 3substituents selected from a C₁₋₆ alkyl group optionally substituted by1 to 3 halogen atoms, a C₁₋₆ alkoxy group optionally substituted by 1 to3 halogen atoms, a halogen atom, a nitro group, a hydroxy group and anamino group; and 3) a C₆₋₁₄ aromatic hydrocarbon group optionally having1 to 3 substituents selected from a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 halogen atoms, a C₁₋₆ alkoxy group optionallysubstituted by 1 to 3 halogen atoms, a halogen atom, a nitro group, ahydroxy group and an amino group; Q is a C₁₋₆ alkylene; ring A is abenzene ring which optionally further has 1 to 3 substituents selectedfrom an alkyl group having 1 to 4 carbon atoms, a hydroxy group, analkoxy group having 1 to 4 carbon atoms, an aralkyloxy group having 7 to10 carbon atoms and a halogen atom; Z is —(CH₂)_(n)—O— wherein n is aninteger of 1 to 3; ring B is a pyridine ring which optionally furtherhas 1 to 3 substituents selected from an alkyl group having 1 to 4carbon atoms, an aryl group having 6 to 14 carbon atoms, a hydroxygroup, an alkoxy group having 1 to 4 carbon atoms, an aralkyloxy grouphaving 7 to 10 carbon atoms and a halogen atom; W is a C₁₋₆ alkylene;and R³ is —OR⁸ wherein R⁸ is a hydrogen atom or an alkyl group having 1to 4 carbon atoms.
 6. The compound of claim 1, which is2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]aceticacid or a salt thereof.
 7. A pharmaceutical composition comprising thecompound of claim 1 or a salt thereof and a pharmacologically acceptablecarrier.
 8. A method for treating diabetes mellitus in a mammal, whichcomprises administering an effective amount of the compound of claim 1or a salt thereof to said mammal.
 9. A production method of a compoundrepresented by the formula

wherein R¹ is an oxazolyl group which may have 1 to 4 substituentsselected from the group consisting of (1) halogen atom, (2) nitro group,(3) an aliphatic hydrocarbon group having 1 to 15 carbon atoms, (4) analicyclic hydrocarbon group having 3 to 12 carbon atoms, (5) an aromatichydrocarbon group having 6 to 14 carbon atoms, (6) an acyl group whichmay have 1 to 3 substituents selected from the group consisting of aC₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms, a C₁₋₆alkoxy group optionally substituted by 1 to 3 halogen atoms, a halogenatom, nitro, hydroxy, and amino, (7) an amino group optionally mono- ordi-substituted by alkyl group having 1 to 10 carbon atoms, alkenyl grouphaving 2 to 10 carbon atoms, cycloalkyl group having 3 to 10 carbonatoms, cycloalkenyl group having 3 to 10 carbon atoms, aryl group having6 to 14 carbon atoms or acyl group having 1 to 13 carbon atoms, (8) ahydroxy group which is optionally substituted by alkyl group having 1 to10 carbon atoms, alkenyl group having 2 to 10 carbon atoms, aralkylgroup having 7 to 13 carbon atoms, acyl group having 1 to 13 carbonatoms or aryl group having 6 to 14 carbon atoms, each of which group mayhave 1 or 2 substituents selected from the group consisting of a halogenatom and an alkoxy group having 1 to 3 carbon atoms, and (9) a thiolgroup which is optionally substituted by alkyl group having 1 to 10carbon atoms, cycloalkyl group having 3 to 10 carbon atoms, aralkylgroup having 7 to 13 carbon atoms, acyl group having 2 to 13 carbonatoms or aryl group having 6 to 14 carbon atoms, wherein the above (3)may have 1 to 3 substituents selected from the group consisting of 1) acycloalkyl group having 3 to 10 carbon atoms, 2) an aryl group having 6to 14 carbon atoms, 3) an aralkyl group having 7 to 9 carbon atoms, 4)an amino group, 5) an amino group mono- or di-substituted by alkyl grouphaving 1 to 4 carbon atoms or acyl group having 2 to 8 carbon atoms, 6)an amidino group, 7) an acyl group having 2 to 8 carbon atoms, 8) acarbamoyl group, 9) a carbamoyl group mono- or di-substituted by alkylgroup having 1 to 4 carbon atoms, 10) a sulfamoyl group, 11) a sulfamoylgroup mono- or di-substituted by alkyl group having 1 to 4 carbon atoms,12) a carboxyl group, 13) an alkoxycarbonyl group having 2 to 8 carbonatoms, 14) a hydroxy group, 15) a C₁₋₆ alkoxy group optionallysubstituted by 1 to 3 halogen atoms, 16) a C₂₋₅ alkenyloxy groupoptionally substituted by 1 to 3 halogen atoms, 17) a cycloalkyloxygroup having 3 to 7 carbon atoms, 18) an aralkyloxy group having 7 to 9carbon atoms, 19) an aryloxy group having 6 to 14 carbon atoms, 20) athiol group, 21) a C₁₋₆ alkylthio group optionally substituted by 1 to 3carbon atoms, 22) an aralkylthio group having 7 to 9 carbon atoms, 23)an arylthio group having 6 to 14 carbon atoms, 24) a sulfo group, 25) acyano group, 26) an azide group, 27) a nitro group, 28) a nitroso group,and 29) a halogen atom, wherein the above (4) and (5) may have 1 to 3substituents selected from the group consisting of 1) a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 halogen atoms, 2) a C₂₋₆ alkenyl groupoptionally substituted by 1 to 3 halogen atoms, 3) a cycloalkyl grouphaving 3 to 10 carbon atoms, 4) an aromatic hydrocarbon group having 6to 14 carbon atoms, 5) an aralkyl group having 7 to 9 carbon atoms, 6)an amino group, (7) an amino group mono- or di-substituted by alkylgroup having 1 to 4 carbon atoms or acyl group having 2 to 8 carbonatoms, 8) an amidino group, 9) an acyl group having 2 to 8 carbon atoms,10) a carbamoyl group, 11) a carbamoyl group mono- or di-substituted byalkyl group having 1 to 4 carbon atoms, 12) a sulfamoyl group, 13) asulfamoyl group mono- or di-substituted by alkyl group having 1 to 4carbon atoms, 14) a carboxyl group, 15) an alkoxycarbonyl group having 2to 8 carbon atoms, 16) a hydroxy group, 17) a C₁₋₆ alkoxy groupoptionally substituted by 1 to 3 halogen atoms, 18) a C₂₋₅ alkenyloxygroup optionally substituted by 1 to 3 halogen atoms, 19) acycloalkyloxy group having 3 to 7 carbon atoms, 20) an aralkyloxy grouphaving 7 to 9 carbon atoms, 21) an aryloxy group having 6 to 14 carbonatoms, 22) a thiol group, 23) a C₁₋₆ alkylthio group optionallysubstituted by 1 to 3 halogen atoms, 24) an aralkylthio group having 7to 9 carbon atoms, 25) an arylthio group having 6 to 14 carbon atoms,26) a sulfo group, 27) a cyano group, 28) an azide group, 29) a nitrogroup, 30) a nitroso group, and 31) a halogen atom; X is a bond; Q is analkylene group having 1 to 20 carbon atoms; Y is an oxygen atom; ring Ais a benzene ring optionally further having 1 to 3 substituents selectedfrom the group consisting of (1) an aliphatic hydrocarbon group having 1to 15 carbon atoms which may have 1 to 3 substituents selected from thegroup consisting of 1) a cycloalkyl group having 3 to 10 carbon atoms,2) an aryl group having 6 to 14 carbon atoms, 3) an aralkyl group having7 to 9 carbon atoms, 4) an amino group, 5) an amino group mono- ordi-substituted by alkyl group having 1 to 4 carbon atoms or acyl grouphaving 2 to 8 carbon atoms, 6) an amidino group, 7) an acyl group having2 to 8 carbon atoms, 8) a carbamoyl group, 9) a carbamoyl group mono- ordi-substituted by alkyl group having 1 to 4 carbon atoms, 10) asulfamoyl group, 11) a sulfamoyl group mono- or di-substituted by alkylgroup having 1 to 4 carbon atoms, 12) a carboxyl group, 13) analkoxycarbonyl group having 2 to 8 carbon atoms, 14) a hydroxy group,15) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen atoms,16) a C₂₋₅ alkenyloxy group optionally substituted by 1 to 3 halogenatoms, 17) a cycloalkyloxy group having 3 to 7 carbon atoms, 18) anaralkyloxy group having 7 to 9 carbon atoms, 19) an aryloxy group having6 to 14 carbon atoms, 20) a thiol group, 21) a C₁₋₆ alkylthio groupoptionally substituted by 1 to 3 carbon atoms, 22) an aralkylthio grouphaving 7 to 9 carbon atoms, 23) an arylthio group having 6 to 14 carbonatoms, 24) a sulfo group, 25) a cyano group, 26) an azide group, 27) anitro group, 28) a nitroso group, and 29) a halogen atom, (2) a hydroxygroup which is optionally substituted by alkyl group having 1 to 10carbon atoms, alkenyl group having 2 to 10 carbon atoms, aralkyl grouphaving 7 to 13 carbon atoms, acyl group having 1 to 13 carbon atoms oraryl group having 6 to 14 carbon atoms, each of which group may have 1to 2 substituents selected from the group consisting of a halogen atomand an alkoxy group having 1 to 3 carbon atoms, (3) halogen atom, (4) anacyl group which may have 1 to 3 substituents selected from the groupconsisting of a C₁₋₆ alkyl group optionally substituted by 1 to 3halogen atoms, a C₁₋₆ alkoxy group optionally substituted by 1 to 3halogen atoms, a halogen atom, nitro, hydroxy, and amino, (5) nitrogroup, and (6) an amino group optionally mono- or di-substituted byalkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10carbon atoms, cycloalkyl group having 3 to 10 carbon atoms, cycloalkenylgroup having 3 to 10 carbon atoms, aryl group having 6 to 14 carbonatoms or acyl group having 1 to 13 carbon atoms; Z is —(CH₂)_(n)—O— (nis an integer of 1 to 8); ring B is a pyridine ring which optionallyfurther has 1 to 3 substituents selected from the group consisting of(1) an aliphatic hydrocarbon group having 1 to 15 carbon atoms which mayhave 1 to 3 substituents selected from the group consisting of 1) acycloalkyl group having 3 to 10 carbon atoms, 2) an aryl group having 6to 14 carbon atoms, 3) an aralkyl group having 7 to 9 carbon atoms, 4)an amino group, 5) an amino group mono- or di-substituted by alkyl grouphaving 1 to 4 carbon atoms or acyl group having 2 to 8 carbon atoms, 6)an amidino group, 7) an acyl group having 2 to 8 carbon atoms, 8) acarbamoyl group, 9) a carbamoyl group mono- or di-substituted by alkylgroup having 1 to 4 carbon atoms, 10) a sulfamoyl group, 11) a sulfamoylgroup mono- or di-substituted by alkyl group having 1 to 4 carbon atoms,12) a carboxyl group, 13) an alkoxycarbonyl group having 2 to 8 carbonatoms, 14) a hydroxy group, 15) a C₁₋₆ alkoxy group optionallysubstituted by 1 to 3 halogen atoms, 16) a C₂₋₅ alkenyloxy groupoptionally substituted by 1 to 3 halogen atoms, 17) a cycloalkyloxygroup having 3 to 7 carbon atoms, 18) an aralkyloxy group having 7 to 9carbon atoms, 19) an aryloxy group having 6 to 14 carbon atoms, 20) athiol group, 21) a C₁₋₆ alkylthio group optionally substituted by 1 to 3carbon atoms, 22) an aralkylthio group having 7 to 9 carbon atoms, 23)an arylthio group having 6 to 14 carbon atoms, 24) a sulfo group, 25) acyano group, 26) an azide group, 27) a nitro group, 28) a nitroso group,and 29) a halogen atom, (2) an aromatic hydrocarbon group having 6 to 14carbon atoms which may have 1 to 3 substituents selected from the groupconsisting of 1) a C₁₋₆ alkyl group optionally substituted by 1 to 3halogen atoms, 2) a C₂₋₆ alkenyl group optionally substituted by 1 to 3halogen atoms, 3) a cycloalkyl group having 3 to 10 carbon atoms, 4) anaromatic hydrocarbon group having 6 to 14 carbon atoms, 5) an aralkylgroup having 7 to 9 carbon atoms, 6) an amino group, (7) an amino groupmono- or di-substituted by alkyl group having 1 to 4 carbon atoms oracyl group having 2 to 8 carbon atoms, 8) an amidino group, 9) an acylgroup having 2 to 8 carbon atoms, 10) a carbamoyl group, 11) a carbamoylgroup mono- or di-substituted by alkyl group having 1 to 4 carbon atoms,12) a sulfamoyl group, 13) a sulfamoyl group mono- or di-substituted byalkyl group having 1 to 4 carbon atoms, 14) a carboxyl group, 15) analkoxycarbonyl group having 2 to 8 carbon atoms, 16) a hydroxy group,17) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen atoms,18) a C₂₋₅ alkenyloxy group optionally substituted by 1 to 3 halogenatoms, 19) a cycloalkyloxy group having 3 to 7 carbon atoms, 20) anaralkyloxy group having 7 to 9 carbon atoms, 21) an aryloxy group having6 to 14 carbon atoms, 22) a thiol group, 23) a C₁₋₆ alkylthio groupoptionally substituted by 1 to 3 halogen atoms, 24) an aralkylthio grouphaving 7 to 9 carbon atoms, 25) an arylthio group having 6 to 14 carbonatoms, 26) a sulfo group, 27) a cyano group, 28) an azide group, 29) anitro group, 30) a nitroso group, and 31) a halogen atom, (3) a hydroxygroup which is optionally substituted by alkyl group having 1 to 10carbon atoms, alkenyl group having 2 to 10 carbon atoms, aralkyl grouphaving 7 to 13 carbon atoms, acyl group having 1 to 13 carbon atoms oraryl group having 6 to 14 carbon atoms, each of which group may have 1to 2 substituents selected from the group consisting of a halogen atomand an alkoxy group having 1 to 3 carbon atoms, (4) halogen atom, (5) anacyl group which may have 1 to 3 substituents selected from the groupconsisting of a C₁₋₆ alkyl group optionally substituted by 1 to 3halogen atoms, a C₁₋₆ alkoxy group optionally substituted by 1 to 3halogen atoms, a halogen atom, nitro, hydroxy, and amino, (6) nitrogroup, and (7) an amino group optionally mono- or di-substituted byalkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10carbon atoms, cycloalkyl group having 3 to 10 carbon atoms, cycloalkenylgroup having 3 to 10 carbon atoms, aryl group having 6 to 14 carbonatoms or acyl group having 1 to 13 carbon atoms; U is a bond; and W isan alkylene group having 1 to 20 carbon atoms; or a salt thereof, whichcomprises subjecting a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, to ahydrolysis reaction in the presence of an acid or a base in an aqueoussolvent.